Foamable vehicles and pharmaceutical compositions comprising aprotic polar solvents and uses thereof

ABSTRACT

The present invention teaches a foamable pharmaceutical and cosmetic compositions comprising an aprotic polar solvent; foam compositions and uses thereof.

This application is a Continuation of U.S. application Ser. No.16/236,704, filed Dec. 31, 2019, which is a Continuation of U.S.application Ser. No. 15/883,134, filed Jan. 30, 2018, which is aContinuation of U.S. application Ser. No. 15/639,114, filed Jun. 30,2017, which is a Division of U.S. application Ser. No. 13/263,201, filedDec. 28, 2011, which is a § 371 National Stage entry ofPCT/IB2010/001126, filed Apr. 28, 2010, which claims priority to U.S.Provisional Application No. 61/173,378, filed Apr. 28, 2009, all ofwhich are incorporated herein by reference.

BACKGROUND

This invention relates to foamable pharmaceutical and cosmeticcompositions and foams, containing aprotic polar solvents and uses.

External topical administration is an important route for theadministration of drugs in disease treatment. Administration into bodycavities is gaining in importance. Many groups of drugs, including, forexample, antibiotic, anti-fungal, anti-inflammatory, anesthetic,analgesic, anti-allergic, corticosteroid, retinoid andanti-proliferative medications are preferably administered in creams andointment.

There are many different types of foams and within each foam type thereare many levels of qualities. For example, the froth on the head ofbeer, lather of shampoo, and lather of shaving cream have been looselydescribed as foam but all are different from one another. Suchdifferences speak to usability applicability. At one end of the cosmeticor pharmaceutical foam spectrum, the foam can be long-lasting and notreadily breakable upon mechanical stimulation like shaving foams. Suchfoams lack suitability for pharmaceutical use since they lather withmechanical stimulation and require washing off. At the other end of thespectrum, the foam can be quick breaking without mechanical stimulationand collapse upon release. Such foams can be inconvenient since they candisappear rapidly before they can be conveniently applied to theintended target. Yet another type of foam is delayed foaming gel whichis expelled as a gel but is said to expand into a type of foam onexposure to body temperature. Such expansion can be slow or delayed andinconvenient. Foams are considered a more convenient vehicle for topicaldelivery of active agents. There are several types of topical foams,including aqueous foams, such as commonly available shaving foams;hydroalcoholic foams; emulsion-based foams, comprising oil and watercomponents; and oleaginous foams, which consist of high oil content. Inskin therapy, oil containing foams are preferred, since oil contributesto skin protection and moisturization, which improve the therapeuticeffect of the formulation. Typically foams are made using liquefiedhydrocarbon gas propellant, such as propane, butane and isobutene, orhydro-fluoro carbon propellants.

Formulations containing aprotic polar solvents, such as Dimethylsulfoxide (“DMSO”), have been occasionally known. However, theseformulations have only been known as creams, gels or liquidformulations. Yet, despite the many benefits of pharmaceutical andcosmetic foam formulations, until now DMSO-containing formulations havenot been developed in a commercial foam form.

SUMMARY

The present invention relates to foamable pharmaceutical and cosmeticcompositions and foams, comprising aprotic polar solvents.

There is provided, easy to use, stable foamable formulations and foamscontaining aprotic polar solvents, with improved delivery properties,especially for treatment of dermal and mucosal tissues.

In one or more embodiments waterless formulations comprising at leastone aprotic polar solvent are provided. In certain embodiments thewaterless formulations are formulated with surfactant. In someembodiments they may also comprise a polymer and or a foam adjuvant. Incertain other embodiments they are formulated without surfactant.Surfactant free formulations may in one or more embodiments comprise apolymer and or a foam adjuvant and preferably both. In one or moreembodiments the aprotic waterless formulation comprises a short chainalcohol. In one or more embodiments the waterless formulation may forman emulsion, for example between a hydrophobic phase and an aproticphase. In certain embodiments the formulation may be a single phaseuntil addition of propellant. In one or more embodiments an emulsion isformed or reformed after addition of hydrophobic propellant.

In one or more other embodiments water comprising formulationscomprising at least one aprotic polar solvent are provided. In certainembodiments the water comprising formulations are formulated withsurfactant. In some embodiments they may also comprise a polymer and ora foam adjuvant. In certain other embodiments they are formulatedwithout surfactant. Surfactant free formulations may in one or moreembodiments comprise a polymer and or a foam adjuvant and preferablyboth. In one or more embodiments the aprotic-aqueous formulationcomprises a short chain alcohol. In one or more embodiments the watercomprising formulation may form an emulsion, for example between ahydrophobic phase and an aqueous aprotic phase. In certain embodimentsthe formulation may be a single phase until addition of propellant. Inone or more embodiments an emulsion is formed or reformed after additionof hydrophobic propellant.

According to one or more embodiments the foamable carrier comprises:

-   1. An aprotic polar solvent;-   2. At least one foaming or stabilizing member, selected from the    group, consisting of:    -   a. a surface-active agent;    -   b. a foam adjuvant; and    -   c. a polymeric agent;    -   and-   3. A liquefied or compressed gas propellant at a concentration of    about 3% to about 25% by weight of the total composition.

According to one or more embodiments the foamable carrier comprises:

-   1. An aprotic polar solvent;-   2. At least one foaming or stabilizing member, selected from the    group, consisting of:    -   a. a surface-active agent;    -   b. a foam adjuvant; and    -   c. a polymeric agent;-   3. At least one solvent, selected from the group, consisting of:    -   a. water    -   b. a protic polar solvent; and    -   c. a hydrophobic carrier;    -   and-   4. A liquefied or compressed gas propellant at a concentration of    about 3% to about 25% by weight of the total composition.

According to one or more embodiments the foamable composition is aqueousand comprises two or more of the foaming or stabilizing members. In oneor more embodiments the composition further comprises one of a proticpolar solvent or a hydrophobic carrier or mixtures thereof.

According to one or more embodiments the foamable carrier iswater-containing (aqueous) and comprises:

-   1. An aprotic polar solvent-   2. At least two foaming or stabilizing members, selected from the    group, consisting of:    -   a. a surface-active agent;    -   b. a foam adjuvant; and    -   c. a polymeric agent;-   3. Water and optionally at least one solvent, selected from the    group, consisting of:    -   a. a protic polar solvent; and    -   b. a hydrophobic carrier;    -   and-   4. A liquefied or compressed gas propellant at a concentration of    about 3% to about 25% by weight of the total composition.

According to one or more certain embodiments the aqueous foamablecarrier is aqueous without a hydrophobic carrier and comprises onestabilizing member comprising a non ionic surfactant with a HLB betweenabout 9 to about 16.

According to one or more embodiments, the foamable composition,comprises a therapeutically effective concentration of an aprotic polarsolvent, which possesses inherent therapeutic properties.

In preferred embodiments, the therapeutic aprotic polar solventcomprises Dimethyl sulfoxide (DMSO).

The carrier or pharmaceutical or cosmetic composition is stored in apressurized canister and when released a foam is formed that isthermally stable, yet breaks easily upon application of shear force. Soin one or more embodiments the foam composition is breakable. Thebreakable foam is thermally stable, yet breaks easily upon applicationof shear force. By thermally stable is meant that the foam is stable fora sufficient period of time—both at room temperature and when applied tothe skin or subjected to at temperature of about 36 C—to facilitate easyand relaxed use and allow for possible distractions or interruptions. Inone or more embodiments the foam is stable for at least about 30 secs,at least about 40 secs, at least about 50 secs, at least about 60 secs,at least about 80 secs, at least about 100 secs, at least about 120secs, at least about 140 secs, at least about 160 secs, at least about180 secs, at least about 210 secs, at least about 240 secs, at leastabout 270 secs or at least about 300 secs.

In one or more alternative embodiments the foam composition isquick-break or thermolabile. The quick-breaking foam is thermallyinstable, and collapses easily upon exposure to body temperature withoutthe need to apply shear force. In one or more embodiments the foam haslow stability or is unstable and collapses in less than about 30 secs,in less than about 25 secs, in less than about 20 secs, in less thanabout 15 secs, in less than about 10 secs, or in less than about 5 secs.Foam can be quick-breaking, for example, wherein the foam formulationcomprises high levels of a short chain alcohol, such as, ethanol.

According to one or more embodiments the concentration of the aproticpolar solvent, about 3% to about 97% by weight of the total composition.

According to one or more embodiments, the composition comprises ahydrophobic carrier; and the composition is an emulsion between thewater/aprotic polar solvent mixture and the hydrophobic carrier.

According to one or more embodiments, the composition is waterless. Insome embodiments the composition is waterless and comprises a proticpolar solvent or a hydrophobic carrier or mixtures thereof. In certainembodiments, the composition is waterless, and the composition is awaterless emulsion between the aprotic polar solvent and the hydrophobiccarrier.

According to one or more embodiments, the composition is substantiallywaterless.

According to one or more embodiments the foamable carrier is non-aqueous(waterless) and comprises:

-   1. An aprotic polar solvent-   2. At least one foaming or stabilizing member, selected from the    group, consisting of:    -   a. a surface-active agent;    -   b. a foam adjuvant; and    -   c. a polymeric agent;-   3. Optionally at least one solvent, selected from the group,    consisting of:    -   a. a protic polar solvent; and    -   b. a hydrophobic carrier;    -   and-   4. A liquefied or compressed gas propellant at a concentration of    about 3% to about 25% by weight of the total composition.

According to one or more embodiments, the foamable carrier issubstantially non-aqueous (substantially waterless), and comprises:

-   -   a) An aprotic polar solvent    -   b) At least one member, selected from the group, consisting of:        -   I. a surface-active agent;        -   II. a foam adjuvant; and        -   III. a polymeric agent;    -   c) Up to about 5% water and optionally a solvent, selected from        the group, consisting of:        -   I. a protic polar solvent; and        -   II. a hydrophobic carrier;            -   and    -   d) A liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.

According to one or more embodiments, the foamable carrier issubstantially waterless, and comprises:

-   -   a) An aprotic polar solvent    -   b) At least one member, selected from the group, consisting of:        -   I. a surface-active agent;        -   II. a foam adjuvant; and        -   III. a polymeric agent;    -   c) At least two solvents, one of which is water selected from        the group, consisting of:        -   IV. Up to about 5% water;        -   V. a protic polar solvent; and        -   VI. a hydrophobic carrier;            -   and    -   d) A liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.

According to one or more embodiments, the composition is alcohol-free,or substantially alcohol-free. According to one or more other certainembodiments the composition is alcoholic.

According to one or more embodiments, the composition is a waterlessfoamable carrier comprising:

-   -   a. DMSO    -   b. At least one foaming or stabilizing member, selected from the        group, consisting of:        -   i. a solid surface-active agent at room temperature having a            HLB of less than about 5;        -   ii. a foam adjuvant;        -   iii. hydroxypropyl methyl cellulose;        -   iv. a surface active agent and a foam adjuvant and or            hydroxypropyl methyl cellulose;        -   v. a surface active agent and a foam adjuvant and a            polymeric agent; and        -   vi. a foam adjuvant and a polymeric agent;    -   c. Optionally or at least one solvent, selected from the group,        consisting of:        -   i. a protic polar solvent; and        -   ii. a hydrophobic carrier;    -   and    -   d. A liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.        wherein the resultant foam formed from the carrier is thermally        stable, yet breaks easily upon application of shear force.

According to one or more embodiments, the hydrophobic solvent comprisesa petrolatum.

According to one or more embodiments, the protic polar solvent comprisesethanol.

According to one or more embodiments, the composition further comprisesurea.

According to one or more embodiments, the composition is a watercontaining foamable carrier comprising:

-   -   a. DMSO    -   b. At least two foaming or stabilizing members, selected from        the group, consisting of:        -   i. a surface-active agent;        -   ii. a foam adjuvant;        -   iii. a polymeric agent; and        -   iv. a foam adjuvant and a polymeric agent;    -   c. Water and optionally or at least one solvent, selected from        the group, consisting of:        -   i. a protic polar solvent; and        -   ii. a hydrophobic carrier;    -   and    -   d. A liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.        wherein the resultant foam formed from the carrier is thermally        stable, yet breaks easily upon application of shear force.

According to one or more embodiments, the water is less than about 5%and the formulation is substantially waterless.

According to one or more embodiments the foamable carrier, furthercomprises an active agent; In one or more additional embodiments, theaprotic polar solvents possesses inherent therapeutic properties andtherefore it can be considered as an “active agent”.

According to one or more embodiments the method of treating a disorderof a mammalian subject, includes:

administering a foamable therapeutic composition to a target site, thecomposition comprising:

-   -   a. An aprotic polar solvent    -   b. At least one foaming or stabilizing member, selected from the        group, consisting of:        -   i. a surface-active agent;        -   ii. a foam adjuvant; and        -   iii. a polymeric agent;    -   c. Optionally or at least one solvent, selected from the group,        consisting of:        -   i. water;        -   ii. a protic polar solvent; and        -   iii. a hydrophobic carrier;            and    -   d. A liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.

According to one or more embodiments the method of treating a disorderof a mammalian subject, includes:

administering a foamable therapeutic composition to a target site, thecomposition comprising:

-   -   1. An aprotic polar solvent;    -   2. At least two members, selected from the group, consisting of:        -   i. a surface-active agent;        -   ii. a foam adjuvant; and        -   iii. a polymeric agent;    -   3. At least one solvent, selected from the group, consisting of:        -   i. water;        -   ii. a protic polar solvent; and        -   iii. a hydrophobic carrier;    -   and    -   4. A liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.

According to one or more embodiments, the method comprises a waterlessfoamable carrier or composition with at least one of a surfactant, apolymer and a foam adjuvant. According to one or more other embodiments,the method comprises a substantially waterless foamable carrier orcomposition with at least one of a surfactant, a polymer and a foamadjuvant and up to about 5% water. According to one or otherembodiments, the method comprises an aqueous carrier or composition withat least two of a surfactant, a polymer and a foam adjuvant.

According to one or more embodiments, the method comprises foamablecarrier or composition, further comprises an active agent.

According to one or more embodiments, the method comprises pre-treatingthe target area with a foamable carrier or composition comprising anagent that can ameliorate or prevent a taste or odor being experiencedafter a DMSO foam is applied to a target. According to one or more otherembodiments, the method comprises treating the target area with afoamable carrier or composition further comprising an agent that canameliorate or prevent a taste or odor being experienced after a DMSOfoam is applied to a target.

According to one or more embodiments the foamable composition, comprisesa therapeutically effective concentration of an aprotic polar solvent,which possesses inherent therapeutic properties.

All % values herein are provided on a weight (w/w) basis.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a Table illustrating increase in skin hydration 4 hours afterapplication of DMSO foamable carriers.

FIG. 2 is a color bar chart illustrating increase in skin hydration 4hours after application of DMSO foamable carriers.

FIG. 3 is a color microscope picture of a foam produced from formulationD30 comprising DMSO and mineral oil.

FIG. 4 is a microscope picture at ×200 of a waterless DMSO foam samplefrom formulation D24 showing a single-phase homogeneous preparation freeof crystals or agglomerations.

FIG. 5 is a Microscope picture at ×200 of an aqueous DMSO foam samplefrom formulation D33 showing a single-phase homogeneous preparation freeof crystals or agglomerations.

DETAILED DESCRIPTION

According to one or more embodiments the present invention includes theembodiments described above in the Summary of the Invention as moreparticularly detailed, specified and exemplified below.

Aprotic Polar Solvent

Solvents can be broadly classified into polar (hydrophilic) and nonpolar(lipophilic). The polarity can be measured as the dielectric constant orthe dipole moment of a compound.

An aprotic solvent is an organic solvent that does not contain an O—H orN—H bond; or does not exchange protons with a substance dissolved in it.In the context herein, the aprotic polar solvent is a solvent with acomparatively high relative permittivity (or dielectric constant),greater than about 15, and a sizable permanent dipole moment, thatcannot donate suitably labile hydrogen atoms to form strong hydrogenbonds; and it is miscible in water. Examples of aprotic polar solvents,suitable according to the present invention include, but are not limitedto dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile,acetone, methyl ethyl ketone, 1,4-Dioxane and tetrahydrofuran (THF).Additional non-limiting examples include N-methylpyrrolidone, pyridine,piperidine, dimethyl ether, hexamethylphosphorotriamide,dimethylformanide, methyl dodecyl sulfoxide, N-methyl-2-pyrrolidone and1-methyl-2-pyrrolidinone) and azone (1-dodecylazacycloheptan-2-one).

An aprotic solvent can be a defoamer in certain embodiments. It can incertain embodiments act to accelerate the breakdown of the foam andreduce its stability. To an extent this may be countered by adding oneor more agents that can stabilize the foam and boost its stability. Forexample, addition of a polymer and or a foam adjuvant can help toimprove the collapse time and likewise slow liquid drainage driven bygravity, which otherwise can and will cause the walls of bubbles to thinand ultimately collapse into adjacent bubble walls that are likewisethinning to form larger bubbles. Examples 1 and 2 indicate, for example,that DMSO is not prone to foaming.

DMSO

Dimethyl sulfoxide (DMSO) is the chemical compound with the formula(CH₃)₂SO. This colorless liquid is an important aprotic polar solventthat dissolves both polar and nonpolar compounds and is miscible in awide range of organic solvents as well as water. It has a distinctiveproperty of penetrating the skin very readily, so that some peoplereport that one can taste it soon after it comes into contact with theskin. In this connection, taking DMSO internally is reported to cause afish- or oyster-like taste or odor in the mouth. With its high polaritycombined with a high dielectric constant, DMSO is known to be anexcellent solvent for polar or polarizable organic compounds, but alsomany acids, alkalis and mineral salts. DMSO is miscible with mostco-solvents. The following table provides certain physicalcharacteristics of DMSO and DMF.

DMSO DMF Dielectric constant (25° C.) 46.4 36.7 Polarity (Debye, 25° C.)4.3 3.8 Boiling point (° C.) 189 153 Flash point (closed cup, ° C) 87 58

DMSO can penetrate the skin and other membranes without damaging themand could carry other compounds into a biological system. DMSO has beenused most widely as a topical analgesic, in a 70% DMSO, 30% watersolution. Laboratory studies suggest that DMSO reduces pain by blockingperipheral nerve C fibers. DMSO also is said to reduce inflammation byseveral mechanisms. It is further an antioxidant—a scavenger of the freeradicals that gather at the site of injury. DMSO also stabilizesmembranes and slows or stops leakage from injured cells and isrecommended for many inflammatory conditions not caused by infection ortumor. Because DMSO increases the rate of absorption of some compoundsthrough organic tissues including skin and nails, it can be used as adrug delivery system.

In one or more embodiments a method is provided to ameliorate or preventpossible side effects of DMSO such as a taste, which has been describedas “garlicy” and a breath odor. As an initial observation although ahigh proportion of DMSO can be present in the formulations because theyare presented as a low density foam it is possible to apply a muchthinner layer and cover the same area with a substantially or muchsmaller amount than a cream or ointment. That being said the positioncan be further improved by first applying to the target area acomposition containing one or more of urea, ethanol, and or lipophiliccompounds and then subsequently applying the DMSO foam to the targetarea. The time interval between the first application and the secondapplication can be about almost immediately afterwards, about 30 secsafterwards, about 1 minute afterwards, about 2 minutes afterwards, about5 minutes afterwards, about 10 minutes afterwards, about 20 minutesafterwards, about 30 minutes afterwards, about 40 minutes afterwards,about 50 minutes afterwards, about 60 minutes afterwards, or sometimeslonger. In one or more embodiments the DMSO presented to the target areasimultaneously with another foam containing one or more ingredientsknown to ameliorate or prevent the taste and odor by using a dualchamber device to apply the two foams such as is described in USpublication 2007/0069046 entitled “MEASURE OF CONTENT FROM A PLURALITYOF CONTAINERS” and incorporated herein by reference. In an alternativeapproach the formulation may itself include one or more ingredientsknown to ameliorate or prevent the taste and odor.

Concentration

In an embodiment the aprotic polar solvent can be incorporated in thefoamable composition of the present invention in a concentration betweenabout 3% and about 98% or between about 10% and about 97%, for exampleabove about 15%, above about 20%, above about 25%, above about 30%,above about 35%, above about; 40%, above about 45%, above about 50%,above about 55%, above about, 60%; above about 70%, above about 80%,above about 90%, or any range between any of the aforesaid amounts; andmore preferably from about 10% to about 60% of at least one aproticpolar solvent.

In certain embodiments, the aprotic polar solvent is DMSO and itsconcentration is in the range between about 30% and about 60%. In anembodiment it is between about 40% to about 50%. In an embodiment,aprotic polar solvent is DMSO and its concentration is about 45%.

In other embodiments, the composition contains more than 60% aproticpolar solvent, and in certain cases, up to about 98% of at least oneaprotic polar solvent.

In one or more embodiments where ever a phrase is used to refer to aconcentration of above X % or below X % it can also include X % or ofabove about X % or below about X % it can also include about X %.

General

In one or more embodiments, the aprotic polar solvent is a combinationof two or more aprotic solvents. In certain embodiments the main aproticsolvent is DMSO.

In one or more embodiments, the aprotic polar solvent is used incombination with a solid aprotic compound. Non limiting examples ofsolid aprotic compounds are octyl methyl sulfoxide, nonyl methylsulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, and dodecylmethyl sulfoxide.

In one or more embodiments, the aprotic polar solvent is used incombination with a sulfoxide derivative which is not aprotic. Nonlimiting examples of non aprotic sulfoxide compounds having hydroxylgroups are 2-hydroxydecyl methyl sulfoxide, 2-hydroxyundecyl methylsulfoxide and hydroxydodecyl methyl sulfoxide.

In one or more embodiments, formulations comprising DMSO can produce aquality foam with one or more surfactants without the addition of apolymer and or without the addition of a foam adjuvant. Aprotic solventsare not oil so which surfactants are preferred is not obvious. In one ormore embodiments preferred surfactants or surfactant combinationsinclude polyoxyethylene fatty acid ethers, polyoxyethylene fatty acidesters, polysorbates, sucrose esters, glycerides esters, sorbitolesters.

In one or more embodiments, formulations comprising DMSO canunexpectedly produce a quality foam without one or more surfactants. Inone or more embodiments good quality waterless foams comprising DMSO canbe achieved with a combination of a polymeric agent and a fatty alcohol.In an embodiment the fatty alcohol may be replaced by the fatty acid. Inan embodiment a combination of fatty alcohol and fatty acid may beapplied together with the polymeric agent.

In one or more embodiments good quality aqueous foams comprising DMSOcan be achieved with a combination of a polymeric agent and a fattyalcohol. In one or more embodiments good quality aqueous foamscomprising DMSO can be achieved with the addition of a short chainalcohol, such as ethanol, even in high concentrations.

By the term “aqueous” in relation to formulations herein it is intendedto indicate and describe a multiplicity of formulations containing somewater including formulations comprising low amounts, medium amounts orhigh amounts of water so as to apply a wide meaning to the term.

Foamable Composition and Foam Properties

The ability to achieve quality foam with substantial concentration of atleast one aprotic polar solvent, is surprising, because usually, suchsolvents are not prone to create a foam. The challenge is not just toachieve a quality foam but also to attain a formulation that willsatisfy a plurality of two, three, four, five, six or more of propertyspecifications simultaneously.

-   -   1. Uniformity: The composition should be formulated so that it        is and can remain uniform without phase separation or        precipitation over time. This property is of high importance        when the product is intended to be a pharmaceutical product.    -   2. Flowability: The composition, when placed in an aerosol        container and pressurized should be flowable such that it can be        expelled through the canister valve. It should preferably also        be shakable inside the container. These requirements create a        formulation challenge, because low or non-viscous flowable and        shakable compositions are prone to undergo phase separation or        precipitation.    -   3. Quality: Upon release from the can, the composition should        generate a foam of about good or excellent quality having low        density and small bubble size.    -   4. Stability/Breakability: The fine balance between stability        and breakability of the foam coming out of the container is very        delicate: on one hand the foam should not be “quick breaking”,        i.e., it should be at least short term stable upon release from        the pressurized container and not break as a result of exposure        to skin temperature; and on the other hand, it should be        “breakable”, i.e., it should spread easily, break down and        absorb into the skin or membrane upon application of mild shear        force.    -   5. Skin Feeling: To ensure patient compliance the skin feeling        after application should be pleasant, and greasy or waxy        residues should be minimalized.    -   6. Non irritating: The above requirements should be achieved        with the awareness that formulation excipients, especially        surfactants, can be irritating, and should be used in low        concentrations.    -   7. Delivery: Finally, the composition should also be designed to        ensure efficient delivery of a therapeutic agent (other than the        aprotic polar solvent) into the target site of treatment.

Based on extensive investigations and trial and error experiments, ithas been found that such properties can be achieved for formulationscomprising water by incorporating into the composition at least twostabilizing members, and also for formulations that are substantiallywaterless by incorporating into the composition at least one stabilizingmember selected from the group consisting of:

-   -   i. a surface-active agent;    -   ii. a foam adjuvant    -   iii. a polymeric agent        It has further been discovered that such properties can be        achieved for waterless formulations by incorporating into the        composition at least one stabilizing member, selected from the        group, consisting of:    -   i. a surface-active agent;    -   ii. a foam adjuvant    -   iii. a polymeric agent

The type, quality, properties and mechanism of foam formation foraprotic formulations cannot be predicted or deduced based on theliterature or on existing product experience. The challenge to achievesuch foam formulations may be even more pronounced when the aproticpolar solvent composition is waterless or substantially waterless.

As detailed and exemplified below, the aqueous or water containingcompositions containing aprotic polar solvents, such as DMSO, conformwith the desirable and favorable sensory properties of foam. Theyfurther deliver efficacious therapy, as exemplified herein.

As further detailed and exemplified below, even waterless orsubstantially waterless compositions, containing aprotic polar solvents,such as DMSO, provide favorable sensory properties of foam.

Surface Active Agent

The composition of the present invention contains a surface-activeagent. Surface-active agents (also termed “emulsifiers” or“surfactants”) include any agent linking oil and water in thecomposition, in the form of emulsion. A surfactant'shydrophilic/lipophilic balance (HLB) describes the emulsifier's affinitytoward water or oil. HLB is defined for non-ionic surfactants. The HLBscale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic),with 10 representing an equal balance of both characteristics. The HLBof a blend of two emulsifiers equals the weight fraction of emulsifier Atimes its HLB value plus the weight fraction of emulsifier B times itsHLB value (weighted average). In many cases a single surfactant maysuffice. In other cases a combination of two or more surfactants isdesired. Reference to a surfactant in the specification can also applyto a combination of surfactants or a surfactant system. As will beappreciated by a person skilled in the art which surfactant orsurfactant system is more appropriate is related to the vehicle andintended purpose. In general terms a combination of surfactants isusually preferable where the vehicle is an emulsion. In an emulsionenvironment a combination of surfactants can be significant in producingbreakable foams of good quality. It has been further discovered that thegenerally thought considerations for HLB values for selecting asurfactant or surfactant combination are not always binding foremulsions and that good quality foams can be produced with a surfactantor surfactant combination both where the HLB values are in or towardsthe lipophilic side of the scale and where the HLB values are in ortowards the hydrophilic side of the scale. Surfactants also play a rolein foam formation where the foamable formulation is a single phasecomposition.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 2 and 9, or morethan one surface active agent and the weighted average of their HLBvalues is between about 2 and about 9. Lower HLB values may in certainembodiments be more applicable, especially in compositions with lowwater content, or non-aqueous compositions.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 7 and 14, or morethan one surface active agent and the weighted average of their HLBvalues is between about 7 and about 14. Mid range HLB values may incertain embodiments be more suitable for oil in water emulsions.

According to one or more other embodiments the composition contains asingle surface active agent having an HLB value between about 9 and 20,or more than one surface active agent and the weighted average of theirHLB values is between about 9 and about 20.

In a waterless or substantially waterless environment a wide range ofHLB values may be suitable; however, surfactants of the low range aresometimes preferred.

Preferably, the composition of the present invention contains anon-ionic surfactant. Nonlimiting examples of possible non-ionicsurfactants include:

-   -   Polyoxyethylene sorbitan esters (polysorbates), such as        Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate),        Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate),        Polysorbate 60 (polyoxyethylene (20) Sorbitan monostearate) and        Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).    -   Sorbitan esters, such as Span 20 (Sorbitan monolaurate), Span 40        (Sorbitan monopalmitate), Span 60 (Sorbitan monostearate), Span        65 (Sorbitan tristearate), Span 80 (Sorbitan monooleate).    -   Polyoxyethylene fatty acid esters, such as, PEG-8 Stearate,        PEG-20 Stearate, PEG-40 Stearate, PEG-100 Stearate, PEG-150        Distearate, PEG-8 laurate, PEG-10 laurate, PEG-12 laurate,        PEG-20 laurate, PEG-8 oleate, PEG-9 oleate, PEG-10 oleate,        PEG-12 oleate, PEG-15 oleate and PEG-20 oleate.    -   PEG-Fatty Acid Diesters, such as PEG-20 dilaurate, PEG-20        dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32        dioleate.    -   Polyethylene glycol (PEG) ethers of fatty alcohols, e.g.,        Isoceteth-20, Laureth-4, Laureth-9, Laureth-23, Ceteth-2,        Ceteth-10, Ceteth-20, Steareth-2, Steareth-7, Steareth-10,        Steareth-20, Steareth-21, Steareth-100, Steareth-200, Oleth-2,        Oleth-3, Oleth-5, Oleth-10, Oleth-20, Ceteareth-6, Ceteareth-12,        Ceteareth-17, Ceteareth-20, Ceteareth-25, Ceteareth-50,        Ceteareth-80, Cetoleth-5, Cetoleth-10, Pareth-12, Pareth-23,        C12-13 Pareth-3, C12-13 Pareth-4.    -   Glycerol esters, such as glyceryl monostearate, glyceryl        monolaurate, glyceryl monopalmitate and glyceryl monooleate    -   PEG-fatty Acid Mono- and di-ester Mixtures—several PEG-fatty        acid esters are marketed commercially as mixtures or mono- and        diesters.    -   Polyethylene Glycol Glycerol Fatty Acid Esters, such as PEG-7        Glyceryl Cocoate, PEG-7 Glyceryl Cocoate, PEG-20 Almond        Glycerides, PEG-12 glyceryl laurate, PEG-20 glyceryl laurate,        PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20        glyceryl oleate, and PEG-30 glyceryl oleate.    -   Alcohol-Oil Transesterification Products such as PEG-5        hydrogenated castor oil, PEG-6 almond oil, PEG-6 caprylic/capric        glycerides, PEG-6 peanut oil, PEG-6 corn oil, PEG-6 apricot        kernel oil, PEG-6 triolein, PEG-7 hydrogenated castor oil, PEG-8        caprylic/capric glycerides, PEG-8 corn oil, PEG-9 hydrogenated        castor oil, PEG-20 corn glycerides, PEG-20 almond glycerides,        PEG-25 hydrogenated castor oil, PEG-25 trioleate, PEG-35 castor        oil, PEG-40 hydrogenated castor oil, PEG-60 corn glycerides,        PEG-60 almond oil, PEG-40 palm kernel oil, PEG-50 castor oil,        PEG-50 hydrogenated castor oil. Also included as oils in this        category of surfactants are oil-soluble vitamins, such as        vitamins A, D, E, K, etc. Thus, derivatives of these vitamins,        such as tocopheryl PEG-100 succinate, are also suitable        surfactants.    -   Polyglycerized Fatty Acids, such as polyglyceryl oleate,        polyglyceryl-2 dioleate, and polyglyceryl-10 trioleate        (hydrophobic); and polyglyceryl-10 laurate, polyglyceryl-10        oleate, and polyglyceryl-10 mono, dioleate (hydrophilic).        Polyglyceryl polyricinoleates are also preferred hydrophilic and        hydrophobic surfactants.    -   Propylene glycol fatty acid esters, such as propylene glycol        monolaurate, propylene glycol ricinoleate, propylene glycol        monooleate, propylene glycol dicaprylate/dicaprate and propylene        glycol dioctanoate.    -   Mono- and diglycerides, such as glyceryl monooleate, glyceryl        ricinoleate, glyceryl laurate, glyceryl dilaurate, glyceryl        dioleate, glyceryl mono/dioleate, glyceryl caprylate/caprate,        caprylic acid mono/diglycerides, and mono- and diacetylated        monoglycerides.    -   Sterol and sterol derivatives, such as PEG-24 cholesterol ether.    -   Sugar esters (mono-, di- and tri-esters of sucrose with fatty        acids), such as sucrose monopalmitate and sucrose monolaurate.    -   Polyethylene glycol alkyl phenols        The following table provides by examples the HLB values of        various non-ionic surfactants, sorted by HLB from lowest        (hydrophobic) to highest (hydrophilic).

Glycol Distearate HLB = 1 PEG-7 Olivate HLB = 11 Sorbitan Trioleate HLB= 1.8 Cetearyl Glucoside HLB = 11 Propylene Glycol Isostearate PEG-8Oleate HLB = 11.6 HLB = 2.5 Polyglycery1-3 Methyglucose Glycol StearateHLB = 2.9 Distearate HLB = 12 Sorbitan Sesquioleate HLB = 3.7 Oleth-10HLB = 12.4 Glyceryl Stearate HLB = 3.8 Oleth-10/Polyoxyl 10 OleylLecithin HLB = 4 Ether NF HLB = 12.4 Sorbitan Oleate HLB = 4.3 Ceteth-10HLB = 12.9 Sorbitan Monostearate NF HLB = 4.7 PEG-8 Laurate HLB = 13Sorbitan Stearate HLB = 4.7 Cocamide MEA HLB = 13.5 Sorbitan IsostearateHLB = 4.7 Polysorbate 60 HLB = 14.9 Steareth-2 HLB = 4.9 Polysorbate 80HLB = 15 Oleth-2 HLB = 4.9 Isosteareth-20 HLB = 15 Glyceryl Laurate HLB= 5.2 PEG-60 Almond Glycerides Ceteth-2 HLB = 5.3 HLB = 15 PEG-30Dipolyhydroxystearate Polysorbate 80 HLB = 15 HLB = 5.5 PEG-20 MethylGlucose Glyceryl Stearate SE HLB = 5.8 Sesquistearate HLB = 15 PEG-4Dilaurate HLB = 6 Ceteareth-20 HLB = 15.2 Methyl Glucose SesquistearateOleth-20 HLB = 15.3 HLB = 6.6 Steareth-20 HLB = 15.3 Sorbitan LaurateHLB = 8.6 Steareth-21 HLB = 15.5 PEG-40 Sorbitan Peroleate HLB = 9Ceteth-20 HLB = 15.7 Laureth-4 HLB = 9.7 Isoceteth-20 HLB = 15.7 PEG-7Glyceryl Cocoate HLB = 10 Polysorbate 20 HLB = 16.7 PEG-20 AlmondGlycerides HLB = 10 Laureth-23 HLB = 16.9 PEG-25 Hydrogenated CastorPEG-100 Stearate HLB = 18.8 Oil HLB = 10.8 Steareth-100 HLB = 18.8Stearamide MEA HLB = 11 PEG-80 Sorbitan Laurate Polysorbate 85 HLB = 11HLB = 19.1

In one or more embodiments of the composition comprises water and asingle stabilizing member, which is at least one surface active agent.In such embodiments the at least one surface active agent is non ionicand can comprise a solid (for example ceteth −20) or liquid surfactant(for example Tween 80) with a HLB between about 9 and about 16. As canbe seen from the results in Example 8 in which a non ionic surfactantalone with a HLB between about 9-16 provides a better foam quality andstability than a non ionic surfactant alone with a HLB value lower thanabout 9 or higher than about 16. However, in order to improve stabilityand collapse time the aqueous formulations comprise a second stabilizingmember, which can be an appropriate polymeric agent (such ashydroxypropyl methylcellulose) and or an appropriate foam adjuvant (suchas cetostearyl alcohol, stearyl alcohol, stearic acid and isostearicacid) or a polymeric agent, which has surfactant properties such as apoloxamer. In certain embodiments a combination of at least twostabilizing members is a synergistic combination, such as observed inExample 9. Also by providing two or more stabilizing members it canallow a wider range of agents and or a broader range of HLB. In one ormore other embodiments the formulation comprises a hydrophobic orlipophilic component and the formulation prior to addition of thepropellant is an emulsion. In such embodiments the surface active agenthas a role in stabilizing the emulsion and a role in generating a stablebreakable foam. Furthermore a system has to be selected such that uponaddition of the propellant the emulsion is not destabilized. Theemulsion can be an oil in water emulsion or if an appropriate surfactantis used such as the following non limiting examples of glycerylstearate, sorbitan stearate, polyglyceryl oleate or other surfactantswith an HLB value lower than about 9, a water in oil emulsion may beformed.

In one or more embodiments the composition is a waterless compositionand a single stabilizing member. The stabilizing member can be at leastone polymeric agent, at least one foam adjuvant or at least one surfaceactive agent. In such embodiments the at least one surface active agentis non ionic and can comprise a solid surface active agent, which is asolid ambient temperature. In one preferred embodiment the surfactantgenerally comprises a linear molecule with a more polar head, forexample sorbitan monostearate and or glyceryl monostearate. It has beenobserved, for example, that when a surfactant with a non linearunsaturated fatty acid chain is used, such as sorbitan monoleate, only abubbly liquid is achieved (See Example 3). This incidentally is incontrast to the position with an aqueous system where for example Tween80 has been used successfully although it has an oleate moiety. Inanother preferred embodiment, in the context of a waterless composition,the surfactant has a low HLB value, being between about 2 and about 9.In certain embodiments, the HLB of the solid surface active agent isbetween about 2 and about 5. It has been surprisingly discovered that asolid surface active agent, having low HLB provides a foam with betterquality and stability than a liquid and/or a high HLB surfactant. It hasbeen further surprisingly discovered that a solid surface active agent,having low HLB evolves a breakable foam of quality, even without anyadditional foam stabilizing agents (such as a polymer or a foamadjuvant).

In one or more embodiments the surface active agent is a combination oftwo or more surface active agents. Such a combination may be in certaincases more effective than a single surfactant and provides a more stableemulsion or improved foam quality. For example and by way ofnon-limiting explanation it has been found that by choosing twosurfactants, one hydrophobic and the other hydrophilic the combinationcan produce a more stable emulsion than a single surfactant. In certainembodiments the combination is a synergistic combination. In one or moreembodiments the difference in the HLB of two surfactants is about atleast 2, or is about at least 3, or is about at least 4.

In one or more embodiments the surfactant can be, a surfactant systemcomprising of a surfactant and a co surfactant, a waxy emulsifier, aliquid crystal emulsifier, an emulsifier which is solid or semi solid atroom temperature and pressure, or combinations of two or more agents inan appropriate proportion as will be appreciated a person skilled in theart. Where a solid or semi solid emulsifier combination is used it canalso comprise a solid or semi solid emulsifier and a liquid emulsifier.

In one or more embodiments the surface-active agent includes at leastone non-ionic surfactant. Ionic surfactants are known to be irritants.Therefore, non-ionic surfactants are preferred in applications includingsensitive tissue such as found in most mucosal tissues, especially whenthey are infected or inflamed. We have surprisingly found that non-ionicsurfactants alone can provide formulations and foams of good orexcellent quality in the carriers and compositions disclosed herein.

Yet, in certain embodiments, the foamable composition includes a mixtureof at least one non-ionic surfactant and at least one ionic surfactant,selected from the group of anionic, cationic, zwitterionic, amphotericand ampholytic surfactants, in a ratio in the range of about 100:1 to6:1. In one or more embodiments, the non-ionic to ionic surfactant ratiois greater than about 6:1, or greater than about 8:1; or greater thanabout 14:1, or greater than about 16:1, or greater than about 20:1. Infurther embodiments, surface active agent comprises a combination of anon-ionic surfactant and an ionic surfactant, at a ratio of between 1:1and 20:1.

In selecting a suitable surfactant or combination thereof it should beborne in mind that the upper amount of surfactant that can be used maybe limited by the shakability of the composition. In general terms, asthe amount of non liquid surfactant is increased the shakability of theformulation reduces until a limitation point is reached where theformulation becomes non shakable and unsuitable. Thus in an embodimentany effective amount of surfactant may be used provided the formulationremains shakable. In other certain exceptional embodiments the upperlimit may be determined by flowability such as in circumstances wherethe composition is marginally or apparently non shakable. Thus in anembodiment any effective amount of surfactant may be used provided theformulation remains flowable.

In certain embodiments the amount of surfactant or combination ofsurfactants is between about 0.05% to about 20%; between about 0.05% toabout 15%; or between about 0.05% to about 10%. In a preferredembodiment the concentration of surface active agent is between about0.2% and about 8%. In a more preferred embodiment the concentration ofsurface active agent is between about 1% and about 6%. In certainembodiments by comprising a second or a second and a third stabilizingmember it is possible to minimize the amount of surfactant used in theformulation, for example such that the surface active agent is betweenabout 0.5% and about 3%.

If the composition as formulated is a substantially non shakablecomposition it is nevertheless possible as an exception in the scopedisclosed herein for the formulation to be flowable to a sufficientdegree to be able to flow through an actuator valve and be released andstill expand to form a good quality foam. This surprising and unusualexception may be due one or more of a number of factors such as the highviscosity, the softness, the lack of crystals, the pseudoplastic or semipseudo plastic nature of the composition and the dissolution of thepropellant into the formulation.

Foam Adjuvant

In one or more embodiments the foamable vehicle further includes a foamadjuvant. More particularly the foam adjuvant is preferably a fatty acidor a fatty alcohol. Foam adjuvants, as defined herein are also useful infacilitating improved spreadability and absorption of the composition.

In one or more embodiments the foam adjuvant includes fatty alcoholshaving 15 or more carbons in their carbon chain, such as cetyl alcoholand stearyl alcohol (or mixtures thereof). Other examples of fattyalcohols are arachidyl alcohol (C20), behenyl alcohol (C22),1-triacontanol (C30), as well as alcohols with longer carbon chains (upto C50).

In one or more embodiments the foam adjuvant includes fatty acids having16 or more carbons in their carbon chain, such as hexadecanoic acid(C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22),octacosanoic acid (C28), as well as fatty acids with longer carbonchains (up to C50), or mixtures thereof. As for fatty alcohols, theamount of fatty acids required to support the foam system is inverselyrelated to the length of its carbon chain.

In one or more embodiments, a combination of a fatty acid and a fattyalcohol is employed.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have at least one double bond. A further class of foam adjuvantincludes a branched fatty alcohol or fatty acid. The carbon chain of thefatty acid or fatty alcohol also can be substituted with a hydroxylgroup, such as 12-hydroxy stearic acid.

An important property of the fatty alcohols and fatty acids used incontext of the composition disclosed herein is related to theirtherapeutic properties per se. Long chain saturated and mono unsaturatedfatty alcohols, e.g., stearyl alcohol, erucyl alcohol, arachidyl alcoholand behenyl alcohol (docosanol) have been reported to possess antiviral,antiinfective, antiproliferative and anti-inflammatory properties (see,U.S. Pat. No. 4,874,794). Longer chain fatty alcohols, e.g.,tetracosanol, hexacosanol, heptacosanol, octacosanol, triacontanol,etc., are also known for their metabolism modifying properties andtissue energizing properties. Long chain fatty acids have also beenreported to possess anti-infective characteristics.

In one or more embodiments, a combination of a foam adjuvant and apolymeric agent is employed. In certain embodiments the combination issynergistic, for example as observed in Example 5 Part B, where stearylalcohol and hydoxypropyl methylcellulose were noted to have asynergistic effect.

In one or more embodiments, a combination of a foam adjuvant and asurface active agent is employed.

In one or more embodiments, a combination of a foam adjuvant and apolymeric agent is employed.

In one or more embodiments, a combination of a foam adjuvant, apolymeric agent and a surface active agent is employed.

Polymeric Agent

In one or more embodiments, the composition disclosed herein contains apolymeric agent selected from the group consisting of a bioadhesiveagent, a gelling agent, a film forming agent and a phase change agent. Apolymeric agent enhances the creation of foam having fine bubblestructure, which does not readily collapse upon release from thepressurized aerosol can. The polymeric agent serves to stabilize thefoam composition and to control drug residence in the target organ. Incertain embodiments the polymer can have surfactant like properties andcontribute to the stabilization of emulsion formulations, such aspoloxamer or pemulen.

Exemplary polymeric agents include, in a non-limiting manner,naturally-occurring polymeric materials, such as locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum,sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guargum, cationic guars, hydroxypropyl guar gum, starch, amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid and hyaluronic acid; chemically modifiedstarches and the like, carboxyvinyl polymers, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acidpolymers, polyvinyl acetate polymers, polyvinyl chloride polymers,polyvinylidene chloride polymers and the like.

Additional exemplary polymeric agents include semi-synthetic polymericmaterials such as cellulose ethers, such as methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer(homopolymer of acrylic acid is crosslinked with an allyl etherpentaerythritol, an allyl ether of sucrose, or an allyl ether ofpropylene, such as Carbopol® 934, Carbopol® 940, Carbopo® 941, Carbopol®980 and Carbopol® 981. Poloxamers (synthetic block copolymer of ethyleneoxide and propylene) such as Poloxamer 124, Poloxamer 188, Poloxamer237, Poloxamer 338 and Poloxamer 407. Other useful Poloxamers are: 181,182, 183, 184, 185, 212, 215, 217, 231, 234, 235, 238, 331, 333, 334,335, 401, 402, and 403. Polyethylene glycol, having molecular weight of1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000) alsohave gelling capacity and they are also considered polymeric agents.

In one or more embodiments the polymer is hydoxypropyl methyl cellulose,for example where the formulation is waterless and a single stabilizingmember is utilized, the polymeric agent comprises hydroxypropyl methylcellulose.

Mixtures of the above polymeric agents are contemplated.

In one or more embodiments the polymer is used in combination withanother stabilizing member, which can be a surfactant and or a foamadjuvant.

The concentration of the polymeric agent should be selected so that thecomposition, after filling into aerosol canisters and pressurized withpropellant, is flowable, and can be shaken in the canister. In one ormore embodiments, the concentration of the polymeric agent is selectedsuch that the viscosity of the composition, prior to filling of thecomposition into aerosol canisters, is less than about 30,000 CP, andmore preferably, less than about 15,000 CP. In one or more embodiments,the viscosity of the composition, prior to filling of the compositioninto aerosol canisters, is less than about 10,000 CP, or less than about5,000 CP, or less than about 3,000 CP.

Combination of a Foam Adjuvant and a Polymeric Agent

Interestingly, when a foam adjuvant (e.g., stearyl alcohol) alone or apolymeric agent (e.g., hydroxypropyl methylcellulose) alone is used withDMSO, a foam of good quality is obtained, but it quickly collapses uponexposure to 36° C. (collapse time 10 and 30 sec respectively), as shownin formulations D21 and D07. However, surprisingly, when these twocomponents are combined with DMSO, they act synergistically to produce agood quality foam with a collapse time of 120 seconds as shown informulation D22 (See Example 5 Part B).

Optional Organic Carriers

Optionally, the foamable composition further includes at least oneorganic carrier selected from the group consisting of a hydrophobicorganic carrier, a petrolatum, an organic protic polar solvent, andmixtures thereof, at a concentration of about 2% to about 50% by weight.

Hydrophobic Solvent/Emollient

One or more hydrophobic solvents are optionally included in thecomposition, in order to add to the sensory properties of thecomposition and/or in order to impart skin conditioning properties. Inan embodiment, the hydrophobic solvent is an emollient, i.e., asubstance that softens and soothes the skin. Emollients are used tocorrect dryness and scaling of the skin. The hydrophobic solvent and/orthe emollient can be selected from the group consisting of mineral oil,alkyl esters of fatty acids such as isopropyl palmitate, isopropylisostearate, diisopropyl adipate, diisopropyl dimerate, octyl palmitate,cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolinalcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryllinoleate, wheat germ glycerides, arachidyl propionate, myristyllactate, decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityltetrastearate, neopentylglycol dicaprylate/dicaprate, isononylisononanoate, isotridecyl isononanoate, myristyl myristate, triisocetylcitrate, octyl dodecanol, maleated soybean oil, unsaturated orpolyunsaturated oils, such as olive oil, corn oil, soybean oil, canolaoil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seedoil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil,salmon oil, flaxseed oil, wheat germ oil, evening primrose oils;essential oils; and silicone oils, such as dimethicone, cyclomethicone,polyalkyl siloxane, polyaryl siloxane, polyalkylaryl siloxane, apolyether siloxane copolymer and apoly(dimethylsiloxane)-(diphenyl-siloxane) copolymer. In certainembodiments the carrier is a petrolatum.

While the aprotic polar solvent and water are generally miscible, when ahydrophobic carrier is included to the composition, it is necessary tocreate an emulsion between the water/aprotic polar solvent mixture andthe hydrophobic carrier. Even when the composition is waterless, thehydrophobic carrier is typically insoluble in the aprotic solvent, andtherefore it is necessary to create an emulsion between the aproticpolar solvent and the hydrophobic carrier.

Protic Polar Solvent

A “protic polar solvent” is an organic solvent that has a hydrogen atombound to an oxygen as in a hydroxyl group or a nitrogen as in an aminegroup. They are typically soluble in both water and oil.

In one or more embodiments, the formulation can comprise a protic polarsolvent.

In one or more embodiments, the protic polar solvent is a polyol.Polyols are organic substances that contain at least two hydroxy groupsin their molecular structure.

In one or more embodiments, the protic polar solvent contains an diol (acompound that contains two hydroxy groups in its molecular structure),such as propylene glycol (e.g., 1,2-propylene glycol and 1,3-propyleneglycol), butanediol (e.g., 1,4-butaneediol), butanediol (e.g.,1,3-butaneediol and 1,4-butenediol), butynediol, pentanediol (e.g.,1,5-pentanediol), hexanediol (e.g., 1,6-hexanediol), octanediol (e.g.,1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol, diethyleneglycol, triethylene glycol, tetraethylene glycol, dipropylene glycol anddibutylene glycol.

In one or more embodiments, the polar solvent contains a triol (acompound that contains three hydroxy groups in its molecular structure),such as glycerin and 1,2,6-Hexanetriol.

Additional examples of protic polar solvents include polyols, such asglycerol (glycerin), propylene glycol, hexylene glycol, diethyleneglycol, propylene glycol n-alkanols, terpenes, di-terpenes,tri-terpenes, terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane,ethylene glycol, other glycols, alkanols, such as dialkylamino acetates,and admixtures thereof, dimethyl isosorbide, ethyl proxitol,dimethylacetamide (DMAc) and alpha hydroxy acids, such as lactic acidand glycolic acid.

According to still other embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200 (MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof.

Lower molecular weight alcohols can sometimes be more potent as asolvent, for example by extracting lipids from the skin layers moreeffectively, which characteristic can adversely affect the skinstructure and cause dryness and irritation. So where a lower molecularweight alcohol is used in a formulation other ingredients are ideallyselected to ameliorate or prevent such side effects.

Many polar solvents, for example propylene glycol and glycerin, possessthe beneficial property of a heumectant.

In one or more embodiments, the polar solvent is a humectant.

Additional Components

In an embodiment, a composition disclosed herein includes one or moreadditional components. Such additional components include but are notlimited to anti oxidants anti perspirants, anti-static agents, bufferingagents, bulking agents, chelating agents, cleansers, colorants,conditioners, deodorants, diluents, dyes, emollients, fragrances, hairconditioners, herbal extracts, humectants, keratolytic agents,pearlescent aids, perfuming agents, permeation enhancers, pH-adjustingagents, preservatives, protectants, skin penetration enhancers,softeners, solubilizers, sunscreens, sun blocking agents, sunlesstanning agents, viscosity modifiers, flavanoids and vitamins. As isknown to one skilled in the art, in some instances a specific additionalcomponent may have more than one activity, function or effect.

Propellants

The composition of the present invention requires the addition of apropellant in order to generate a foam. In one or more embodiments thepropellant makes up between about 3% and about 45% or between about 3%and about 35% of the foamable composition, preferably between about 5%and about 25% of the composition. In preparing the formulations theingredients other than propellant are combined to 100% and thepropellant is added thereafter so that the ratio of formulation topropellant can range from 100:3 to 100:45 or from 100:3 to 100:35 orpreferably 100:5 to 100:25. In the case of bag in can where thepropellant is separate from the composition any amount can be used thatis sufficient to drive the contents of the bag out of the canister. Incertain embodiments the propellant in the bag can be the same as and incertain other embodiments be different from the propellant in thecomposition.

Suitable propellants include volatile hydrocarbons such as butane,propane, isobutene or mixtures thereof. In one or more embodiments ahydrocarbon mixture AP-70 is used. Hydrofluorocarbon (HFC) propellantsare also suitable as propellants in the context disclosed herein.Exemplary HFC propellants include 1,1,1,2 tetrafluorethane (Dymel 134),and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). Dimethyl ether is alsouseful. In one or more embodiments use of compressed gases (e.g., air,carbon dioxide, nitrous oxide, and nitrogen) is also possible. Chlorofluorocarbon propellants on the other hand are no longer consideredsuitable for use in cosmetic, pharmaceutical and other formulations dueto inter alia the potential environmental damage that they can do.

In one or more embodiments a combination of at least two propellants,selected from HFC, hydrocarbon propellants, dimethyl ether andcompressed gases is contemplated.

In one or more embodiments the propellant can also be used to expelformulation using a bag in can system or a can in can system as will beappreciated by someone skilled in the art. In certain embodiments thepart of the propellant system is in the formulation and part separatefrom the formulation. In this way it is possible to reduce the amount ofsurfactant in the formulation but still provide good expulsion from thecanister, where the foamable formulation is expelled quickly but withoutjetting or noise.

Alcohol Free

According to one or more embodiments, the foamable composition issubstantially alcohol-free, i.e., free of short chain alcohols. Shortchain alcohols, having up to 5 carbon atoms in their carbon chainskeleton and one hydroxyl group, such as ethanol, propanol, isopropanol,butanol, iso-butanol, t-butanol and pentanol, are considered lessdesirable solvents or polar solvents due to their skin-irritatingeffect. Thus, the composition is substantially alcohol-free and includesless than about 5% final concentration of lower alcohols, preferablyless than about 2%, more preferably less than about 1%.

Alcoholic

According to one or more certain other embodiments, the foamablecomposition includes a short chain alcohol. In a preferred embodimentthe short chain alcohol is ethanol. In one embodiment the composition iswaterless. In another embodiment it is aqueous or water containing andin a further embodiment it is substantially non-aqueous. In variousembodiments the amount of short chain alcohol is about or above about5%, about or above about 10%; about or above about 15% about or aboveabout 20%. In one or more embodiments the range of short chain alcoholis between about 5% to about 25%. In certain embodiments when shortchain alcohol is present the formulation is breakable and notthermolabile or substantially not thermolabile. By substantially notthermolabile is meant that the foam upon expulsion onto a warm bodysurface at about 35-37° C. does not collapse rapidly within about 30seconds. In one or more alternative embodiments the formulation isthermolabile.

In one or more alternative embodiments the formulation comprises highamounts of short chain alcohol. In certain embodiments the amount ofshort chain alcohol is about or above about 25%, is about or above about30%, is about or above about 35%, is about or above about 40%; is aboutor above about 45%, is about or above about 50%; is about or above about55% or is about or above about 60%.

In one or more embodiments there is provided a composition comprising anaprotic polar solvent and a protic polar solvent, in which the proticpolar solvent can be a short chain alcohol. Such a combination mayconceivably contribute to directed skin delivery of active agents.

Aprotic-Aqueous Formulations

In certain cases, the active agent is soluble in the presence of water,and therefore, in such cases the presence of water in the compositioncan be desirable. In certain preferred embodiments, the compositioncomprises only a small amount of water. In other embodiments water is asubstantial component. In one or more embodiments the range of water canbe from about 0.1% to about 5%, or from about 5% to about 15%, or fromabout 15% to about 25%, or from about 25% to about 35%, or from about35% to about 45%, or from about 45% to about 55%, or from about 55% toabout 65%, or from about 55% to about 65%, or from about 65% to about75%, or from about 75% to about 85% or from about 5% to about 85%, orfrom about 10% to about 75%. In one or more embodiments the formulationcan be aprotic-hydroalcoholic.

Waterless Formulations

In certain cases, the active agent degrades in the presence of water,and therefore, in such cases the presence of water in the composition isnot desirable. Thus, in certain preferred embodiments, the compositionis substantially non-aqueous. The term “substantially non-aqueous” or“substantially waterless” is intended to indicate that the compositionhas water content below about 5%, preferably below about 2%, such asbelow about 1.5%. In certain other preferred embodiments the compositionis non aqueous or waterless.

By non aqueous or waterless is meant that the composition contains no orsubstantially no, free or unassociated or absorbed water. It will beunderstood by a person of the art that the waterless solvents andsubstances miscible with them disclosed herein can be hydrophilic andcan contain water in an associated or entrapped or absorbed form and mayabsorb water from the atmosphere and the ability to do so is itshygroscopic water capacity. It is intended that essentially non-aqueousformulations are included within its scope such that the formulationsmay have present a small amount of water. In some embodiments thecomposition ingredients are pretreated to reduce, remove or eliminateany residual or associated or absorbed water.

Modulating Agent

In one or more embodiments the formulation includes a modulating agent,The term modulating agent is used to describe an agent which can improvethe stability of or stabilize a foamable carrier or composition and oran active agent by modulating the effect of a substance or residuepresent in the carrier or composition.

In one or more embodiments the substance or residue may for example beacidic, basic or a buffer system and potentially alter an artificial pHin a waterless or substantially non-aqueous environment or it may be oneor more metal ions which may act as a potential catalyst in a waterlessor substantially non aqueous environment. In various certain embodimentsit may be an ionization agent or an anti oxidization agent or aflavanoid or mixtures thereof that are effective in a waterless orsubstantially non aqueous environment. The modulating agent may in oneor more embodiments act to modulate the ionic or polar characteristicsand any acid-base balance of a waterless or substantially non-aqueouscarrier, composition, foamable carrier or foamable composition orresultant foam disclosed herein.

In one or more other embodiments the modulating agent is used todescribe an agent which can affect pH in an aqueous solution. The agentcan be any of the known buffering systems used in pharmaceutical orcosmetic formulations as would be appreciated by a man of the art. Itcan also be an organic acid, a carboxylic acid, a fatty acid an aminoacid, an aromatic acid, an alpha or beta hydroxyl acid an organic baseor a nitrogen containing compound.

In certain embodiments the substance or residue may be one or more metalions which may act as a potential catalyst in a aqueous environment. Invarious certain embodiments it may be an ionization agent or an antioxidization agent or a flavanoid or mixtures thereof that are effectivein an aqueous environment. The modulating agent may in one or moreembodiments act to modulate the ionic or polar characteristics and anyacid-base balance of an aqueous carrier, composition, foamable carrieror foamable composition or resultant foam disclosed herein.

In certain embodiments the formulation is an emulsion. The emulsion maybe formed prior to the addition of propellant or upon the introductionof propellant. The emulsion may be a waterless emulsion or it may be anaqueous emulsion (oil in water or oil in water). In various certainembodiments the substance or residue may for example be acidic or basicand potentially alter pH in an emulsion environment or it may be one ormore metal ions which may act as a potential catalyst in an emulsionenvironment. In various certain embodiments it may be an ionizationagent or an anti oxidization agent or a flavanoid or mixtures thereofthat are effective in an emulsion environment. The modulating agent mayin one or more embodiments act to modulate the ionic or polarcharacteristics and any acid-base balance of an emulsion carrier,composition, foamable carrier or foamable composition or resultant foamdisclosed herein.

In one or more further embodiments the modulating agent is a chelatingor sequestering or complexing agent that is sufficiently soluble orfunctional in the solvent to enable it to “mop up” or “lock” metal ions.In one or more embodiments a preferred non limiting example is EDTA.

In other embodiments the modulating agent is a buffer, as defined by VanSlyke [Van Slyke, J. Biol. Chem. 52, 525 (1922)], as “a substance whichby its presence in solution increases the amount of acid or alkali thatmust be added to cause unit change in pH.”

Modulating agents may be added to the compositions of the subjectinvention, preferably from about 0.1% to about 10%, more preferably fromabout 1% to about 5%, of the composition. Where the active agent itselfis the modulating agent alone or in combination with another modulatingagent it will be added at an effective dose which may be outside theseranges. For example azelaic acid may be at about 15% of the composition.

It is important to maintain skin surface pH in order to preventsusceptibility to bacterial skin infections or skin damage and disease.Thus, adding a modulating agent, which contributes to the stabilizationof skin pH at the desirable level, is advantageous.

In the same fashion, adding an acidic modulating agent to a foamablecomposition, which is intended for vaginal application is advantageous,since better protection against vaginal infection is attained with pHlower than about 4.5.

Non-limiting examples of antioxidants/radical scavengers are ascorbicacid and derivatives, tocopherol or derivatives thereof (succinate, orsorbate or acetate or other esters), propyl galate, butylated hydroxytoluene and butyl hydroxy anisol. Non-limiting examples of positiveionization agents are benzyl conium chloride, and cetyl pyridiumchloride. Non-limiting examples of negative ionization agents are sodiumlauryl sulfate, sodium lauryl lactylate and phospholipids.

A non-limiting list of flavanoid compounds is: benzquercin, diosmin,ethoxazorutoside, flavodate, sodium hesperidin, leucocianido,monoxerutin, oxerutin, quercetin, rutoside, rosmarinic acid.

In one or more embodiments the modulating agent is mixture orcombination of two or more modulating agents.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamablecarrier is very easy to use. When applied onto the afflicted bodysurface of mammals, i.e., humans or animals, it is in a foam state,allowing free application without spillage. Upon further application ofa mechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

In one or more embodiments the foamable composition has an acceptableshelf-life of at least six months or at least one year, or preferably,at least two years at ambient temperature.

The foamable compositions according to the present invention are stablechemically and physically. For example as seen in Example 14 followingaccelerated stability studies, the foam met the specified stability andassay criteria. The high quality foams disclosed herein can demonstratedesirable texture; can form fine bubble structures that do not breakimmediately upon contact with a surface, and can spread easily on thetreated area and can absorb quickly.

The composition should also preferably be free flowing, to allow it toflow through the aperture of the container, e.g., and aerosol container,and create an acceptable foam.

Foam Quality

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

Breakability

A further aspect of the foam is breakability. The balance betweenstability and breakability of the foam coming out of the container isvery delicate: on one hand the foam should not be “quick breaking”,i.e., it should be stable upon release from the pressurized containerand not break as a result of exposure to skin temperature; and on theother hand, it should be “breakable”, i.e., it should spread easily,break down and absorb into the skin or membrane upon application of mildshear force. The foam is thermally stable, yet breaks under shear force.Shear-force breakability of the foam is clearly advantageous overthermally induced breakability. Thermally sensitive foams immediately orquickly collapse upon exposure to skin temperature and, therefore,cannot be usefully applied on the hand and afterwards delivered to theafflicted area since transfer would have to be effected immediately.

Breakable foam is a specialized low density type of foam that is stableon release at least in the short time span of about minutes, but canbreak readily upon the application of shear force such as gentle rubbingto spread easily over a target surface. Unlike other types of foams,breakable foam is not thermolabile, nor does it display late orlong-delayed expansion over minutes.

Foam Density

Another property of the foam is density (specific gravity), as measuredupon release from the aerosol can. Typically, foams have specificgravity of about 0.20 g/mL or less, such as less than about 0.20 g/mL;or less than about 0.12 g/mL; or less than about 0.10 g/mL; or less thanabout 0.08 g/mL, depending on their composition and on the propellantconcentration.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. Shakability is describedfurther in the section on Tests.

Collapse Time

The collapse time of foam represents its tendency to betemperature-sensitive and its ability to be at least short term stableso as to allow a user sufficient time to comfortably handle and applythe foam to a target area without being rushed and or concerned that itmay rapidly collapse, liquefy and or disappear. Collapse time isexamined by dispensing a given quantity of foam and photographingsequentially its appearance with time during incubation at 36° C. Thus,it is useful for selecting foam products, which are “breakable” but not“quick breaking”, which maintain structural stability at skintemperature for at least a reasonable period of time. In one or moreembodiments it can be about more than a minute, about more than twominutes, about more than 3 minutes, about more than 4 minutes, aboutmore than 5 minutes or longer. In one or more limited embodiments it canbe shorter than one minute, for example about more than 50 seconds,about more than 40 seconds and occasionally about more than 30 seconds.In a preferred embodiment it can be more than about one minute and in amore preferred embodiment it can be more than about 3 minutes. Collapsetime can also provide an indication of the rate of drainage in the foamformulation of the fluid around the bubbles under the influence ofgravity. Short collapse times indicate fast or rapid drainage, whilstlong collapse times indicate slow drainage.

Pharmaceutical Composition

The foamable composition is an ideal vehicle for active pharmaceuticalingredients and active cosmetic ingredients. In the context activepharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents”. In one or moreembodiments the composition comprises a therapeutically effectiveconcentration of at least one active agent. In one or more embodimentsthe composition comprises at least two therapeutic agents. In certainembodiments the aprotic formulation facilitates the combination ofactive agents otherwise unstable in water, which for example areunstable at different pH's.

Suitable active agents include but are not limited to an active herbalextract, an acaricides, an age spot and keratose removing agent, anallergen, an alpha hydroxyl acid, an analgesic agent, an antiacne agent,an antiallergic agent, an antiaging agent, an antibacterial agent, anantibiotic, an antiburn agent, an anticancer agent, an antidandruffagent, an antidepressant, an antidermatitis agent, an antiedemic anent,an antifungal agent, an antihistamine, an antihelminth agent, anantihyperkeratolyte agent, an anti-infective agent, an antiinflammatoryagent, an antiirritant, an antilipemic agent, an antimicrobial agent, anantimycotic agent, an antioxidant, an antiparasitic agent, anantiproliferative agent, an antipruritic agent, an antipsoriatic agent,an antirosacea agent, an antiseborrheic agent, an antiseptic agent, anantiswelling agent, an antiviral agent, an anti-wart agent, ananti-wrinkle agent, an antiyeast agents, an astringent, a beta-hydroxyacid, benzoyl peroxide, a topical cardiovascular agent, achemotherapeutic agent, a corticosteroid, an immunogenic substance, adicarboxylic acid, a disinfectant, a fungicide, a hair growth regulator,a haptene, a hormone, a hydroxy acid, an immunosuppressant, animmunoregulating agent, an immunomodulator, an insecticide, an insectrepellent, a keratolytic agent, a lactam, a local anesthetic agent, alubricating agent, a masking agent, a metals, a metal oxide, a mitocide,a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a protein, a photodynamic therapyagent, a radical scavenger, a refatting agent, a retinoid, a sanative, ascabicide, a self tanning agent, a skin protective agent, a skinwhitening agent, a steroid, a steroid hormone, a vasoconstrictor, avasodilator, a vitamin, a vitamin A, a vitamin A derivative, a vitaminB, a vitamin B derivative, a vitamin C, a vitamin C derivative, avitamin D, a vitamin D derivative, a vitamin D analog, a vitamin F, avitamin F derivative, a vitamin K, a vitamin K derivative, a woundhealing agent and a wart remover. As is known to one skilled in the art,in some instances a specific active agent may have more than oneactivity, function or effect.

Encapsulation of an Active Agent

In one or more embodiments, the active agent is encapsulated inparticles, microparticles, nanoparticles, microcapsules, microsphres,nanocapsules, nanospheres, liposomes, niosomes, polymer matrix,silica-gel, graphite, nanocrystals or microsponges. Such particles canhave various functions, such as (1) protection of the drug fromdegradation; (2) modification of the drug release rate from thecomposition; (3) control of skin penetration profile; and (4) mitigationof adverse effects, due to the controlled release of the active agentfrom the encapsulation particles.

Solubility of an Active Agent

In an embodiment, the active agent is not fully soluble in water or, isnot fully soluble in the presence of a hydrophobic solvent in theformulation, or is not fully soluble in the oil phase of the emulsion.In one or more embodiments the active agent is soluble in thecomposition or a phase thereof. In one or more embodiments the activeagent is insoluble in water and wherein the active agent is solubilizedthe in the composition. In an embodiment, the aprotic polar solvent ispresent in the composition in an amount sufficient to solubilize theactive agent in the composition. In one or more embodiments, aproticpolar solvent acts to improve the solubility of an active agent. Incertain preferred embodiments, the active agent to be solubilized isselected from the group consisting of a non-steroidal anti-inflammatoryagent, a local anesthetic agent, a steroid, an immunomodulators, akeratolytically active agent, an anti-acne agent, an anti-rosacea agent,an antiinfective agent and an anti-psoriasis agent. In a preferredembodiment the active agent to be solubilized is diclofenac. In one ormore embodiments a protic solvent acts to improve solubility of anactive agent. In one or more embodiments the delivery of the activeagent is improved by the aprotic solvent and or protic solvent.

In one or more embodiments the active agent is intended for transdermaldelivery. In certain embodiments the aprotic polar solvent in includedin the composition in a concentration which is sufficient to increasethe rate of absorption of such active agent through organic tissuesincluding skin and nails.

Exemplary Groups of Active Agents

NSAID

In an embodiment, the active agent is a non-steroidal anti-inflammatoryagent. In the context a nonsteroidal antiinflammatory agent (also termedherein “NSAID”) is a pharmaceutically active compound, other than acorticosteroid, which affects the immune system in a fashion thatresults in a reduction, inhibition, prevention, amelioration orprevention of an inflammatory process and/or the symptoms ofinflammation and or the production pro-inflammatory cytokines and otherpro-inflammatory mediators, thereby treating or preventing a diseasethat involves inflammation.

In one or more embodiments, the NSAID is an inhibitor of thecyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are knowntoday: the constitutive cyclooxygenase (COX-1); and the induciblecyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or moreembodiments, the NSAID is selected from the group consisting of a COX-1inhibitor, a COX-2 inhibitor or a non-selective NSAID, whichsimultaneously inhibits both COX-1 and COX-2.

In one or more embodiments, the NSAID is salicylic acid a salicylic acidderivatives. Exemplary salicylic acid derivative include, in a nonlimiting fashion, aspirin, sodium salicylate, choline magnesiumtrislicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine, olsalazine, esters of salicylic acid with a carboxylicacid, esters of salicylic acid with a dicarboxylic acid, esters ofsalicylic acid with a fatty acid, esters of salicylic acid with ahydroxyl fatty acid, esters of salicylic acid with an essential fattyacid, esters of salicylic acid with a polycarboxylic acid, and anycompound wherein salicylic acid is linked to an organic moiety through acovalent bond.

In one or more embodiments, the NSAID is para-aminophenol (e.g.,acetaminophen) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an indole or an indole-aceticacid derivative (e.g., indomethacin, sulindac, etodolac) and salts andderivatives thereof.

In one or more embodiments, the NSAID is an aryl acetic acids (e.g.,tolmetin, diclofenac, ketorolac) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an arylpropionic acid and saltsand derivatives thereof. Exemplary arylpropionic acid derivativeinclude, in a non limiting fashion, are ibuprofen, naproxen,flubiprofen, ketoprofen, fenoprofen, oxaprozin.

In one or more embodiments, the NSAID is anthranilic acids or ananthranilic acid derivative, also termed “fenamates” (e.g., mefenamicacid, meclofenamic acid) and salts and derivatives thereof.

In one or more embodiments, the NSAID is selected from the group ofenolic acids, enolic acid salts, enolic acid esters, amides, anhydridesand salts and derivatives thereof. Non-limiting examples of enolic acidderivatives include oxicams (piroxicam, tenoxicam) andpyrazolidinediones (phenylbutazone, oxyphenthratrazone)

Yet, in additional embodiments, the NSAID is an alkanone (e.g.,nabumetone).

Selective COX-2 Inhibitors include, in an exemplary mannerdiaryl-substituted furanones (e.g., Rofecoxib); diaryl-substitutedpyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac); andsulfonanilides (e.g., Nimesulide) and salts and derivatives thereof.

In an embodiment, the aprotic polar solvent is present in thecomposition in an amount sufficient to solubilize the NSAID, asexemplified herein by the solubilization of diclofenac.

Local Anesthetic Agents

In an embodiment, the active agent is a local anesthetic agent. Withoutlimiting the scope of the invention, the anesthetic agent can beselected from the group consisting of benzocaine, lidocaine,bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine,tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine,pramoxine, phenol, any pharmaceutically acceptable salts thereof andmixtures of such anesthetic agents. Any mixture of synergisticallybeneficial anesthetic agents is contemplated. In an embodiment, theaprotic polar solvent is present in the composition in an amountsufficient to solubilize the anesthetic agent.

Steroids

In an embodiment, the active agent is a steroid. In certain embodimentsthe steroid is a corticosteroid, including but not limited to,bydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, aswell as analogs, derivatives, salts, ions and complexes thereof.

In certain embodiments, the steroid is a hormone or a vitamin, asexemplified by pregnane, cholestane, ergostane, aldosterone,androsterone, calcidiol, calciol, calcitriol, calcipotriol,clomegestone, cholesterol, corticosterone, cortisol, cortisone,dihydrotestosterone, ergosterol, estradiol, estriol, estrone,ethinylestradiol, fusidic acid, lanosterol, prednisolone, prednisone,progesterone, spironolactone, timobesone and testosterone, as well asanalogs, derivatives, salts, ions and complexes thereof.

In an embodiment, the aprotic polar solvent is present in thecomposition in an amount sufficient to solubilize the steroid.

Keratolytically Active Agents

A keratolytic agent may be included as an active agent of a foamablecomposition. The term “keratolytically active agent” as used hereinincludes a compound that loosens and removes the stratum corneum of theskin, or alters the structure of the keratin layers of skin.Keratolytically active agents are used in the treatment ofdermatological disorders that involve dry skin, hyperkeratinization(such as psoriasis), skin itching (such as xerosis), acne and rosacea.

Suitable keratolytically active agents include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. As such, they areused in the treatment of dermatological disorders. Dihydroxybenzene andderivatives thereof have been recognized as potent keratolytic agents.Resorcinol (m-dihydroxybenzene) and derivatives thereof are used inanti-acne preparations. In addition to hydroquinone (p-dihydroxybenzene)having anti-pigmentation properties, hydroquinone is also known to bekeratolytic. These compounds also exhibit antiseptic properties. Cresolsalso possess bactericidal and keratolytic properties.

Vitamin A and vitamin A derivatives, also termed herein “retinoids”,such as retinoic acid, isoretinoic acid, retinol and retinal are anotherclass of keratolytically active agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as salicylic acid(o-hydroxybenzoic acid) and salicylic acid salts and pharmaceuticallyacceptable derivatives.

Another class of keratolytically active agents includes urea and ureaderivatives.

Immunomodulators

In an embodiment, the active agent is an immunomodulator.Immunomodulators are chemically or biologically-derived agents thatmodify the immune response or the functioning of the immune system.Immunomodulators suitable for use according to the present inventioninclude, among other options, cyclic peptides, such as cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus,laquinimod and imiquimod, as well as analogs, derivatives, salts, ionsand complexes thereof. Such compounds, delivered in the foam, areespecially advantageous in skin disorders such as psoriasis, eczema andatopic dermatitis, where the large skin areas are to be treated. In anembodiment, the aprotic polar solvent is present in the composition inan amount sufficient to solubilize the immunomodulator.

Retinoids

In an embodiment, the active agent is a retinoid. Retinoids suitable foruse according to the present invention include, among other options,retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene,13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene,lycopene, 9-cis-beta-carotene, lutein and zeaxanthin, as well asanalogs, derivatives, salts, ions and complexes thereof.

Anti-Acne and Anti-Rosacea Active Agents

In an embodiment, the active agent is an anti-acne or an anti-rosaceaagent. The anti-acne agent can be selected from the group consisting ofresorcinol, sulfur, salicylic acid and salicylates, alpha-hydroxy acids,nonsteroidal anti-inflammatory agents, benzoyl peroxide, retinoic acid,isoretinoic acid and other retinoid compounds, adapalene, tazarotene,azelaic acid and azelaic acid derivatives, antibiotic agents, such aserythromycin and clyndamycin, coal tar, zinc salts and complexes, andcombinations thereof, in a therapeutically effective concentration.

Antipsoriasis Agents

In an embodiment, the active agent is an anti-psoriasis agent. Suchanti-psoriasis agent can be selected, among other options, from thegroup of keratolytically-active agents, salicylic acid, coal tar,anthralin, corticosteroids, vitamin D and derivatives and analogsthereof, including vitamin D3 analogs such as calcitriol, calcipotriol;retinoids, such as tazarotene and photodymamic therapy agents.

Antiinfective Agents

In an embodiment, the active agent is an anti-infective agent. Suchanti-infective agent can be selected from the group of an antibioticagent, an antibacterial agent, an antifungal agent, an agent thatcontrols yeast, an antiviral agent and an antiparasitic agent. Exemplaryantiinfective agents are exemplified by beta-lactam antibiotic, anaminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole,metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin,clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxinB, an antibiotic polyene, an antibiotic polyether, an antibioticquinolone, an antibiotic steroid, fucidic acid, mupirocin,chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal,silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, anoxidizing agent, iodine, iodate, a periodate, a hypochlorite, apermanganate, a substance that release free radicals and/or activeoxygen, a cationic antimicrobial agent, a quaternary ammonium compound,a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymericbiguanide and a naturally occurring antibiotic compound, as well asanalogs, derivatives, salts, ions and complexes thereof.

Aprotic Polar Solvents with Therapeutic Properties

In certain embodiments, the aprotic polar solvent possesses therapeuticproperties on its own and therefore, it can be regarded as “activeagent”. For example, DMSO acts as a topical analgesic, it reduces painand it also reduces inflammation by several mechanisms. It is anantioxidant—a scavenger of the free radicals that gather at the site ofinjury.

Because aprotic polar solvents, such as DMSO increases the rate ofabsorption of some compounds through organic tissues including skin andnails, formulations comprising such aprotic polar solvents can be usedas a drug delivery system.

Fields of Applications

The foamable carrier is suitable for treating any inflicted surface. Inone or more embodiments, foamable carrier is suitable for administrationto the skin, a body surface, a mucosal surface and a body cavity, e.g.,the cavity and/or the mucosa of the nose, mouth, eye, ear, respiratorysystem, vagina or rectum (severally and interchangeably termed herein“target site”).

By selecting a suitable active agent, or a combination of two or moreactive agents, the foamable composition is useful in treating an animalor a human patient having any one of a variety of dermatologicaldisorders, including dermatological pain, dermatological inflammation,acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acnefulminans, nodular papulopustular acne, acne conglobata, dermatitis,bacterial skin infections, fungal skin infections, viral skininfections, parasitic skin infections, skin neoplasia, skin neoplasms,pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas,cutaneous abscesses, necrotizing subcutaneous infections, scalded skinsyndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing moistens, gangrene, scarring, and vitiligo.

Likewise, the foamable composition is suitable for treating a disorderof a body cavity or mucosal surface, e.g., the mucosa of the nose,mouth, eye, ear, respiratory system, vagina or rectum. Non limitingexamples of such conditions include chlamydia infection, gonorrheainfection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV),genital warts, bacterial vaginosis, candidiasis, chancroid, granulomaInguinale, lymphogranuloma venereum, mucopurulent cervicitis (MPC),molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis,vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvardystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis,pelvic inflammation, endometritis, salpingitis, oophoritis, genitalcancer, cancer of the cervix, cancer of the vulva, cancer of the vagina,vaginal dryness, dyspareunia, anal and rectal disease, analabscess/fistula, anal cancer, anal fissure, anal warts, Crohn's disease,hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation,polyps of the colon and rectum.

In an embodiment the composition is useful for the treatment of aninfection. In one or more embodiments, the composition is suitable forthe treatment of an infection, selected from the group of a bacterialinfection, a fungal infection, a yeast infection, a viral infection anda parasitic infection.

In an embodiment the composition is useful for the treatment of wound,ulcer and burn.

In an embodiment the target site is selected from the group consistingof the skin, a body cavity, a mucosal surface, the nose, the mouth, theeye, the ear canal, the respiratory system, the vagina and the rectum.

The composition is also suitable for administering a hormone to the skinor to a mucosal membrane or to a body cavity, in order to deliver thehormone into the tissue of the target organ, in any disorder thatresponds to treatment with a hormone.

In an embodiment the target site is selected from the group consistingof the skin, a body cavity, a mucosal surface, the nose, the mouth, theeye, the ear canal, the respiratory system, the vagina and the rectum.In an embodiment the disorder is selected from the group consisting ofdermatological pain, dermatological inflammation, acne, acne vulgaris,inflammatory acne, non-inflammatory acne, acne fulminans, nodularpapulopustular acne, acne conglobata, dermatitis, bacterial skininfections, fungal skin infections, viral skin infections, parasiticskin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis,acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,necrotizing subcutaneous infections, scalded skin syndrome,folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing myositis, gangrene, scarring, and vitiligo, chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranuloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum; and whereinthe active agent is suitable for treating said disorder.

In one embodiment the disorder is an inflammation, skin inflammation,acne, rosacea, actinic keratosis, skin cancer, a local pain, joint painand ostheoarthritis; the active agent is a nonsteroidalanti-inflammatory drug, given at a therapeutically effectiveconcentration.

In one embodiment the disorder is psoriasis; the active agent is avitamin D, a vitamin D derivative, a vitamin D analog, a vitamin D3analog (such as calcitriol and calcipotriol) given at a concentrationbetween about 0.0001% and about 0.02% by weight.

In one embodiment the active agent is permethrin. In a Preferredembodiment it is at a concentration between about 1% and about 8% byweight.

Cosmetic Use

In one or more embodiments, the aprotic polar solvent foamable carriermay be used for cosmetic use. For example it may be used as part of acosmetic formulation to prevent a cosmetic disorder or to improve theskin. Alternatively it may be used with cosmetic effect for example as acosmetic remover. Unexpectedly, it has been found that foam containingaprotic solvents displays advantages over the prior art removers. It canbe dispensed in small quantities as a foam targeted to a surface andapplied locally with mechanical force causing the foam to break. Theaprotic solvent can then solubilize the cosmetic which can then be andremoved for example using a cloth. The foam is short term stable andavoids the mess, spills and over use of liquid aprotic solvents.

The following examples further exemplify the aprotic polar solventfoamable pharmaceutical carriers, pharmaceutical compositions thereof,cosmetic carriers, cosmetic compositions thereof, methods for preparingthe same, and uses of the compositions. The examples are for thepurposes of illustration only and are not intended to be limiting of theinvention. Many variations may be carried out by one of ordinary skillin the art and are contemplated within the full scope disclosed herein.

In one embodiment the foamable compositions and foams are suitable foruse in treating, ameliorating, reducing or preventing a dermatological,cosmetic or mucosal disorder. More particularly, they are suitable foruse where such disorders would otherwise be less responsive when treatedwith one agent alone.

Methods/Tests

General Manufacturing Procedures

The following procedures are used to produce the foam samples describedin the examples below, in which only the steps relevant to eachformulation are performed depending on the type and nature ofingredients used.

A) Waterless Formulations

Step 1: Gelling agents, if present, are added to the aprotic polarsolvent at room temperature under mixing until formulation homogeneityis obtained.

Step 2: The mixture/solvent is warmed to about 50-60° C., surfactantsand/or foam adjuvants, if present, are added under agitation untilcomplete dissolution.

Step 3: Hydrophobic and/or hydrophilic solvents, if present are heatedto 50-60° C. and added under mixing until formulation homogeneity isachieved.

Step 4: The mixture is cooled down to room temperature andtemperature-sensitive agents (e.g., active agents), humectants,preservatives, pH-buffering agents or cosmetic agents, if present, areadded under mixing until dissolution.

Step 5: The formulation is packaged in aerosol canisters which arecrimped with a valve, pressurized with propellant and equipped with anactuator suitable for foam dispensing.

B) Aqueous or Water Containing Formulations

Step 1: Water is added to the aprotic polar solvent at room temperature.Gelling agents, if present, are added to the mixture at room temperatureunder mixing until formulation homogeneity is obtained.

Step 2: The mixture/aqueous solvent is warmed to about 50-60° C.,surfactants and/or foam adjuvants, if present, are added under agitationuntil complete dissolution.

Step 3: Hydrophobic and/or hydrophilic solvents, if present, are heatedto 50-60° C. and added under mixing until formulation homogeneity isachieved (to form an emulsion).

Step 4: The mixture is cooled down to room temperature andtemperature-sensitive agents (e.g., active agents), humectants,preservatives, pH-buffering agents or cosmetic agents, if present, areadded under mixing until dissolution.

Step 5: The formulation is packaged in aerosol canisters which arecrimped with a valve, pressurized with propellant and equipped with anactuator suitable for foam dispensing.

Materials

TABLE 1 Exemplary possible ingredients suitable for the production offoamable compositions disclosed herein. Chemical Commercial NameFunction Name Supplier Carbomer 934P Gelling agent Carbomer 934PSpectrum Carbomer copolymer Gelling agent Pemulen TR-2 Noveon Type ACeteth 2 Surfactant Brij 52 Fluka Ceteth 20 Surfactant Lipocol C20 LipoCetostearyl alcohol Foam Speziol C16-C18 Cognis adjuvant Diclofenacsodium Active agent Diclofenac sodium Sriken Dimethyl Sulfoxide SolventDimethyl Sulfoxide Fluka Ethanol absolute Solvent Ethanol J. T BakerGlycerin Humectant Glycerin Cognis Glycerol Surfactant Cutina GMS CognisMonostearate Hydroxypropyl Gelling agent Klucel EF Hercules celluloseHydroxypropyl Gelling agent Methocel K100M Colorcon methylcellulose DowLight Mineral Oil Solvent Light Liquid Gadot Paraffin Minocycline HClActive agent Minocycline HCl Hovione Paraffin Wax Thickener; Paraffin51-53 Merck Stabilizer PEG-100 Stearate Surfactant Myrj 59P UniqemqaPetrolatum, White Solvent Sofmetic LMP MMP Poloxamer 188 Gelling agentLutrol F68 BASF Poloxamer 407 Gelling agent Lutrol F127 BASFPolyglyceryl Oleate Surfactant Plurol Oleique Gattefosse CC497Polysorbate 80 Surfactant Tween 80 Croda Propane/Isobutane/ PropellantAP-70 Aeropress Butane (55:18:27) Corporation Propylene glycol HumectantPropylene Glycol Gadot Sorbitan Monooleate Surfactant Span 80 SpectrumSorbitan Monostearate Surfactant Span 60 Degussa Steareth-2 SurfactantSympatens Kolb AS/020G Stearic Acid Foam Edenor ST1 Cognis adjuvantStearyl Alcohol Foam Speziol C18 Cognis adjuvant Terbinafine HCl Activeagent Terbinafine HCl Taro Urea Humectant carbamide Gadot Xanthan GumGelling agent Xanthan Gum 11K CP Kelco USProduction Under Vacuum

Optionally, the foamable carrier may be produced under nitrogen andunder vacuum. Whilst the whole process can be carried out under anoxygen free environment, it can be sufficient to apply a vacuum afterheating and mixing all the ingredients to obtain an emulsion orhomogenous liquid. Preferably the production chamber is equipped toapply a vacuum but if not the formulation can be for example placed in adesiccator to remove oxygen prior to filing and crimping.

Canisters Filling and Crimping

Each aerosol canister is filled with the pre-foam formulation (“PEE”,i.e., foamable carrier) and crimped with valve using vacuum crimpingmachine. The process of applying a vacuum will cause most of the oxygenpresent to be eliminated. Addition of hydrocarbon propellant may withoutbeing bound by any theory further help to reduce the likelihood of anyremaining oxygen reacting with the active ingredient. It may do so,without being bound by any theory, by one or more of dissolving in theoil or hydrophobic phase of the formulation, by dissolving to a verylimited extent in the aqueous phase, by competing with some oxygen fromthe formulation, by diluting out any oxygen, by a tendency of oxygen tooccupy the dead space, and by oxygen occupying part of the space createdby the vacuum being the unfilled volume of the canister or thatremaining oxygen is rendered substantially ineffective in theformulation.

Pressurizing

Pressurizing is carried out using a hydrocarbon gas or gas mixture.Canisters are filled and then warmed for 30 seconds in a warm bath at50° C. and well shaken immediately thereafter.

Tests

By way of non-limiting example stability tests are briefly set out belowas would be appreciated by a person of the art.

Collapse Time

Collapse time (CT) is examined by dispensing a given quantity of foamand photographing sequentially its appearance with time duringincubation at 36° C. It is useful for evaluating foam products, whichmaintain structural stability at skin temperature for at least 1 minute.Foams which are structurally stable on the skin for at least one minuteare termed “short term stable” carriers or foams.

Density

In this procedure, the foam product is dispensed into vessels (includingdishes or tubes) of a known volume and weight. Replicate measurements ofthe mass of foam filling the vessels are made and the density iscalculated. The canister and contents are allowed to reach roomtemperature. Shake the canister to mix the contents and dispense anddiscard 5-10 mL. Then dispense foam into a pre-weighed tube, filling ituntil excess is extruded. Immediately remove (level off) excess foam atboth ends and weigh the filled tube on the weighing balance.

Viscosity

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜>50,000 CP, the viscosity at 1 RPM may be measured, although thefigures are of a higher magnitude.

Chemical Stability

The amount of active agent present is analyzed in foam expelled fromvarious pressurized canisters containing foam formulations using HPLC.Analysis is carried out at zero time and at appropriate time intervalsthereafter. The canisters are stored in controlled temperatureincubators at one or more of 5 C, at 25 C, at, 40 C and at 50 C. Atappropriate time intervals canisters are removed and the amount ofactive agent in the foam sample is measured.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubbles size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital cameraequipped with a macro lens. The diameter of about 30 bubbles is measuredmanually relatively to calibration standard template. Statisticalparameters such as mean bubble diameter, standard deviation andquartiles are then determined. Measuring diameter may also be undertakenwith image analysis software. The camera used was a Nikon D40X Camera(resolution 10 MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mmF2.8 EX DG HSM). Pictures obtained are cropped to keep a squared regionof 400 pixels×400 pixels.

Microscopic Observation

The light microscope enables observing and measuring particles from fewmillimeters down to one micron. Light microscope is limited by thevisible light wavelength and therefore is useful to measuring size ofparticles above 800 nanometers and practically from 1 micron (1,000nanometers).

When foam is examined under a microscope for the presence of particles,crystals or agglomerates, for example, a cover slide is carefully placedover a small foam sample and pressure is applied to the cover causingmost of the bubbles to break. Some of the foam bubbles can sometimesstill be observed in the formulations, as can be seen in FIG. 3. Thefluid under the cover slide can then be viewed to identify whether ornot there are any particles, crystals or agglomerates.

Shakability

Shakability represents the degree to which the user is able to feel/hearthe presence of the liquid contents when the filled pressurized canisteris shaken. Shaking is with normal mild force without vigorous shaking orexcessive force. When the user cannot sense the motion of the contentsduring shaking the product may be considered to be non-shakable. Thisproperty may be of particular importance in cases where shaking isrequired for affecting proper dispersion of the contents.

Shakability Scoring:

Good shakability (conforms to required quality 2 specification) Moderateshakability (conforms to required quality 1 specification) Not shakable(fails to meet required quality 0 specification) but may still beflowable and allow foam formation of quality Is substantially not ableto pass through valve Block

EXAMPLES

The invention is described with reference to the following examples.This invention is not limited to these examples and experiments. Manyvariations will suggest themselves and are within the full intendedscope.

Section A—Waterless Aprotic Foamable Vehicles Example 1—WaterlessComposition Containing Dimethyl Sulfoxide (“DMSO”) Alone

% w/w Formulation D01 Ingredients Dimethyl Sulfoxide (DMSO) 100.0 Total100.0 Propellant AP-70 10.0 Foam Properties Foam Quality Poor CollapseTime (sec) 0

Comments: Formulation DO1 did not give a foam, but a bubbly liquid. DMSOalone does not have self-foaming or foam-boosting properties. Theresults may also suggest a defoaming effect or role of aprotic solvents.

Example 2—Waterless Compositions Containing Dimethyl Sulfoxide andVarious Polymeric (Gelling) Agents

Part A % w/w Formulations D02 D03 D04 D05 D06 Ingredients DimethylSulfoxide 99.0 98.0 98.0 95.0 98.0 Xanthan Gum 1.0 — — — — Hydroxypropylcellulose — 2.0 — — — Pemulen TR-2 — — 2.0 — — Poloxamer 188 — — — 5.0 —Carbomer 934P — — — — 2.0 Total 100.0 100.0 100.0 100.0 100.0 PropellantAP-70 10.0 10.0 10.0 10.0 10.0 Foam Properties Foam Quality Poor FairFair Fair Fair Collapse Time (sec) 0 5 30 5 0

Comments: Various different gelling agents were mixed with DMSO. Withthe exception of xanthan gum, all the other polymers dissolved in DMSOto form liquid gels prior to the addition of propellant. Xanthan did notdissolve and remained as a powder. Compositions D02 to D06, merelyproduced either bubbly liquids or very watery foams that rapidlycollapse and not of quality. The results may also indicate a defoamingeffect or role of aprotic solvents.

Part B % w/w Formulations D07 D08 Ingredients Dimethyl Sulfoxide 99.599.0 Hydroxypropyl methylcellulose K100M 0.5 1.0 Total 100.0 100.0Propellant AP-70 10.0 10.0 Foam Properties Foam Quality Good GoodCollapse Time (sec) 30 45

Comments: Surprisingly, the addition of hydroxypropyl methylcellulose toDMSO improves the foam quality and gave good quality foams. In contrasthydroxypropyl cellulose without the methyl group even with 4 times theconcentration does not produce a foam of quality with DMSO. Moreover,and increase in the hydroxypropyl methylcellulose concentration from0.5% to 1% improved the foam collapse time from 30 sec to 45 sec. Thereis however still is a need for a longer collapse time to improve ease ofapplication on the skin. In one or more embodiments the polymeric orgelling agent is hydroxypropyl methylcellulose.

Part C % w/w Formulations D22B D22C Ingredients Dimethyl Sulfoxide 95.099.0 Hydroxypropyl methylcellulose K100M — 0.5 Parrafin 51-53 5.0 5.0Total 100.0 100.0 Propellant AP-70 10.0 10.0 Foam Properties FoamQuality Poor Poor Collapse Time (sec) Immediate Immediate

Comments: Whilst it was shown above in Part B that the addition ofhydroxypropyl methylcellulose to DMSO can improve foam quality andgenerate good quality foam it can been seen here that in the presence ofparaffin wax hydroxypropyl methylcellulose was ineffective and poor foamwas produced.

Example 3—Waterless Compositions Containing Dimethyl Sulfoxide andSurface Active Agents

Physical % w/w Formulations HLB state D09 D10 D11 D12 D13 D14 D15 D16Ingredients Dimethyl — Liquid 97.0 97.0 97.0 97.0 97.0 97.0 97.0 94.0Sulfoxide Tween 80 15.0 Liquid 3.0 — — — — — — — Ceteth 20 15.7 Solid —3.0 — — — — — 3.0 Polyglyceryl 6.0 Liquid — — 3.0 — — — — — OleateSorbitan 4.3 Liquid — — — 3.0 — — — — Monooleate Ceteth 2 5.3 Solid — —— — 3.0 — — 3.0 Sorbitan 4.7 Solid — — — — — 3.0 — — MonostearateGlycerol 3.8 Solid — — — — — — 3.0 — Monostearate Total — — 100 100 100100 100 100 100 100 Propellant AP- — Gas 10.0 10.0 10.0 10.0 10.0 10.010.0 10.0 70 Foam Properties Foam Quality — — Poor Fair Poor Poor GoodGood Excellent Good Collapse Time — — 0 5 0 0 10 >180 >180 10 (sec)

Comments: Various different non-ionic surfactants (surface activeagents) were dissolved into DMSO. As shown in formulations D09 to D12,the addition of several surfactants of various HLB values and physicalstates (solid vs. liquid) merely produced either bubbly liquids or verywatery foams that rapidly collapse and not of quality. Formulations D13and D16 gave good quality foams, but they quickly collapsed and turnedinto bubbly liquids. Combining linear surfactants one with a high HLBand one with a low HLB (see D16) did not appear to result in anyimprovement. Therefore, it is not obvious how to create good qualitybreakable foams with random addition of surfactants.

However, very surprisingly, the addition of sorbitan monostearate orglycerol monostearate to DMSO dramatically improved the foam quality andgood to excellent quality breakable foams were produced, which did notcollapse after 180 sec of incubation at 36° C. Upon application to atarget site and a simple rub of the foams with the hand, these qualityfoams broke, spread evenly over the skin and were readily absorbed intothe skin. For waterless formulations a solid surfactant with a low HLBis preferred.

It can be noted that sorbitan monostearate and glycerol monostearateshare some common properties: both of them are solids at roomtemperature; have a linear fatty acid chain; a polar head(glycerol/sorbitan) and have an HLB value smaller that 5.0. Each one ofthese properties taken alone is not sufficient to create a good qualitybreakable foam, as described in formulations D09 to D12 and D16. Butwithout being bound by any theory it is thought that when the propertiesof solid at room temperature, low HLB, linear hydrophobic chain with apolar head are combined, they act synergistically to create good toexcellent quality breakable foams as shown in formulations D14 and D15.In one or more embodiments the surface active agent is a solid with alow HLB. In further embodiments the surface active agent may include alinear hydrophobic chain and a polar head.

Example 4—Waterless Foamable Compositions Containing Dimethyl Sulfoxide,Surface Active Agents and Examples of Different Active Agents

% w/w Formulations D17 D18 D19 Ingredients Dimethyl Sulfoxide 92.0 96.096.0 Glycerol Monostearate 3.0 3.0 3.0 Diclofenac 5.0 — — MinocyclineHCl — 1.0 — Terbinafine — — 1.0 Total 100.0 100.0 100.0 Propellant AP-7010.0 10.0 10.0 Foam Properties Foam Quality Good Good Good Collapse Time(sec) >180 >180 >180 Presence of drug crystals None* None* None* *Whilstthe API was dissolved some very few surfactant crystals were noted. Inone or more embodiments crystals are eliminated or substantiallyeliminated. By way of non limiting example a co-solvent or aco-surfactant may be added to dissolve the crystals or the amount ofagent may be reduced to an optimal level where the crystals dissolve.

Comments: Several active pharmaceutical agents (“API”) were dissolvedinto stock formulation D15 described above, containing DMSO and glycerolmonostearate. As shown in formulations D17 to D19, the addition ofvarious drugs gave good quality breakable foams which did not collapseafter 180 sec of incubation at 36° C. Moreover, microscopic observationof foam samples revealed the API's were dissolved in these formulations.It follows that the API bioavailability should be improved if dissolvedsince the DMSO can then aid penetration

Example 5—Waterless Compositions Containing Dimethyl Sulfoxide andCombinations of Foam Adjuvants, Polymeric with and without SurfaceActive Agents

Part A - With Surface Active Agents % w/w Formulations D26 D23 D24 D25D15 D55 Ingredients Dimethyl Sulfoxide 94.0 94.0 93.5 96.5 97 DimethylFormamide — — — — — 97 Stearyl Alcohol 3.0 3.0 3.0 — — — GlycerolMonostearate — 3.0 3.0 3.0 3.0 3.0 Tween 80 3.0 — — — — — Hydroxypropyl— — 0.5 0.5 — — methylcellulose K100M Total 100.0 100.0 100.0 100.0100.0 100.0 Propellant AP-70 10.0 10.0 10.0 10.0 10.0 10.0 FoamProperties Foam Quality Good Good Good Good Excellent Poor Collapse Time(sec) 10 >180 >180 >180 >180 0

Comments: A foam adjuvant (stearyl alcohol) was dissolved into DMSO andused with a surfactant Tween. Although the formulation produced a goodquality foam it collapsed almost immediately. As shown in FormulationD26, the random combination of a foam adjuvant and a surfactant does notachieve satisfactory results in terms of foam quality and stability,showing the need for an appropriate selection of the foam stabilizingcomponents as taught in this disclosure. Replacing Tween with glycerolmonostearate produced quality foam with a collapse time of more thanthree minutes. In the presence of glycerol monostearate the addition ofa foam adjuvant or a gelling agent produced no significant change in themeasured parameters. Thus, formulations D23, D24 and D25 describecombinations of two or more stabilizing components appropriatelyselected from the group consisting of a surfactant; a foam adjuvant anda gelling agent that gave good quality breakable foams that did notcollapse after 180 sec at 36° C.

There are advantages to combine one or both of foam adjuvants andgelling agents with surfactants, as this can inter alia bring; a higherformulation viscosity and structure which is suitable for formulationswhich are to contain a suspension of non-dissolved active agents andthus provide a more homogeneous API suspension; an improved foaming; amore stable emulsion; greater stability when the propellant is addedinto the formulation, although adding an inappropriate combination ortoo high viscosity can lead to destabilization on addition of propellantsuch that successful combinations and the amounts are non obvious inorder to achieve a foam of quality and a stable foamable formulation.Moreover, achieving a specific type of foam and foam properties iscertainly non obvious. Nevertheless, in one or more embodiments thecombination of foam adjuvants and gelling agents with surfactants mayenable a decrease in the surfactant concentration without anydegradation of the foam properties. Such a decrease in surfactantconcentration can be desirable in topical applications, as lower levelscan avoid or minimize potential irritation, particularly if theformulations are to be used on sensitive targets such as wounds or bodycavities. Moreover, such combinations have been unexpectedly observed toproduce surprising synergetic effects.

Formulation D55 containing Dimethylformamide in contrast to what wassurprisingly observed with DMSO fails to give a foam of acceptablequality, showing that not all aprotic polar solvents are suitable to beused at high concentrations in combination with glyceryl monostearate.

Part B - Without Surface Active Agents % w/w Formulations D20 D21 D07D22 Ingredients Dimethyl Sulfoxide 97.0 97.0 99.5 96.5 Stearyl Alcohol —3.0 — 3.0 Stearic Acid 3.0 — — — Hydroxypropyl methylcellulose — — 0.50.5 K100M Total 100.0 100.0 100.0 100.0 Propellant AP-70 10.0 10.0 10.010.0 Foam Properties Foam Quality Poor Good Good Good Collapse Time(sec) 0 10 30 120

A foam adjuvant was dissolved in DMSO instead of a surfactant. As seenfrom formulations D20 and D21, the addition of stearic acid to DMSO gavea bubbly liquid whereas the addition of stearyl alcohol gave a goodquality foam but that collapsed almost immediately after 10 sec.

Interestingly, both stearyl alcohol and hydroxypropyl methylcellulosewhen used separately with DMSO give good quality foams that quicklycollapse, after 10 and 30 sec respectively, as seen in formulations D21and D07. But very surprisingly, when these two components are combinedwith DMSO, they act synergistically to produce a good quality foam witha substantially improved collapse time of 120 seconds as seen informulation D22.

In one or more embodiments there is provided a surfactant-free foamformulation comprising DMSO, and fatty alcohols and polymeric agents. Inone or more alternative embodiments there is provided a surfactant-freefoam formulation comprising DMSO, and fatty alcohols essentially free ofpolymeric agents. In one or more other embodiments there is provided asurfactant-free foam formulation comprising DMSO and polymeric agentsessentially free of fatty alcohols.

Example 6—Comparison of Waterless Foamable Vehicle CompositionsContaining DMSO and Urea/Ethanol/Lipophilic Compound with a ControlFormulation Containing Water and a Classic Emulsion Foam Formulation

PART A - DMSO Formulations % w/w % w/w % w/w % w/w Formulation D27 D50D52 D51 Ingredients Dimethyl Sulfoxide 45.0 45.0 45.0 45.0 Glycerin(humectant) 15.0 15.0 15.0 15.0 Propylene glycol 15.0 15.0 15.0 15.0(humectant) Ethanol 20.0 — — — Urea — 20.0 — — Petrolatum — — 20.0 —Water — — — 20.0 Cetostearyl alcohol 1.5 1.5 1.5 1.5 Steareth-2 2.0 2.02.0 2.0 Hydroxypropyl 1.5 1.5 1.5 1.5 cellulose EF Total 100.0 100.0100.0 100.0 Propellant AP-70 8.0 8.0 8.0 8.0 Foam properties FoamQuality Good to Good Good Good Excellent Shakability Good Good Good GoodDensity NM 0.034 0.097 0.063 Collapse NM >180 180 >180 Any after tasteNM No Very Slight Yes Any Breath odour NM No Very Slight Yes NM = NotMeasured

Comments: Formulations D27 is an example of a waterless foam of good toexcellent quality containing 45% DMSO, Ethanol, humectants, a foamadjuvant, a low HLB solid surfactant and a gelling agent. It can benoted that the addition of about 20% of ethanol did not appear to affectthe foam stability or quality.

A preliminary study was run with formulations D50, D51 and D52 todetermine whether any formulations can prevent the known side effect ofor after taste and breath odor after use of DMSO. These DMSO sideeffects were observed to be suppressed when urea is added to theformulation (see D50), are unexpectedly greatly reduced in case ofpetrolatum (see D52), but are still present when water is added to theformulation (see D51). Thus, in one or more embodiments, there areprovided DMSO formulations that are useful in reducing after taste andbreath odor side effects.

Comments: All the formulations D50, D51, D52, produced good to excellentquality foam with low density and good collapse time. To determine whichformulations would be compatible and suitable for use with human skinand their hydration effect, if any, double blind corneometer studieswere carried out to determine the skin-hydration effect of theformulations.

Part B—Manufacturing Procedure

Formulation D50:

-   -   1) Add Hydroxypropyl cellulose EF to water at room temperature        while mixing to “Gel”.    -   2) Heat to 50-60° C. and add Cetostearyl alcohol and Steareth-2        while mixing to dissolution.    -   3) Add slowly Glycerin anhydrous and Propylene glycol while        mixing to homogeneity.    -   4) Cool to RT and add slowly Urea while mixing to homogeneity.    -   5) Complete water if necessary to 100%        Formulation D51:    -   1) 2) 3) and 5) as above; 4) Cool to room temperature and add        slowly water while mixing to homogeneity.        Formulation D52:    -   1) 2) 3) and 5) as above; 4) Cool to room temperature and add        slowly Petrolatum while mixing to homogeneity.        Formulation D27:    -   1) 2) 3) and 5) as above; 4) Cool to room temperature and add        slowly Ethanol while mixing to homogeneity.        Part C—Corneometer Study

Comparison of Formulations D50, D51, D52 with DMSO and a ClassicEmollient tested for skin hydration.

Classic Emollient % w/w Isopropyl myristate 6.00 Glycerol monostearate0.50 PEG-40 stearate 3.00 Stearyl alcohol 1.00 Xanthan gum 0.30 MethocelK100M 0.30 Polysorbate 80 1.00 Water 81.30 Preservative 0.60 Total100.00 Propellant AP70 8.00

Skin hydration is measured using a Corneometer® CM 825 instrument.(Courage+Khazaka, Koln, Germany). The measuring principle of theCorneometer® CM 825 is based on capacitance measurement of dielectricmedium. Any change in the dielectric constant due to skin surfacehydration alters the capacitance of a measuring capacitor. It is capableof detecting even slight changes in the skin hydration level.

Study Flow chart is shown below:

STUDY ACTIVITY Baseline* 4 hours Inclusion/exclusion criteria XApplication of the test X preparations Assessment of skin hydration XAssessment of tolerability X parameters and Adverse Events

Skin hydration level is assessed at baseline with the Corneometer® CM825. The formulations are applied in designated chambers under occlusionfor 4 hours which are then removed and the skin cleaned. Hydration isthen measured.

Study protocol: The study was performed in a temperature controlled room(20-24° C.). Subjects washed their arms with water (no soap) and driedtheir arms with dry paper towel. Formulations were applied using testchambers. The location of each chamber within the stripe was marked onceapplied (maximum of 6 stripes on each arm). Each stripe contained onlyone formulation. One stripe served as a control, non treated area.Formulations, control products and control non treated areas wererandomly assigned to the treatment sites according to a randomizationlist, provided by the study statistician. The application array wasunknown to the study operator and subjects. An amount of approximately 4mg (40 ul) of each of the study formulations was applied on thetreatment sites as described by the randomization list. Skin hydrationlevel was assessed at baseline T=0 (minimum 15 minutes following rinse),using the Corneometer® CM 825, and tested based on study design.

Healthy subjects were applied with single dose of formulations D50, D51,and D52 as shown in Part A above and the emollient formulation herein.As shown in FIG. 1 and FIG. 2, quite unexpectedly the formulations withDMSO have a substantial moisturizing effect when compared with thecontrol and with the Classic Emollient. No significant difference can beseen from the addition of Urea, Petrolatum and Water to the DMSO basedformulations. It can be appreciated that the moisturizing effect doesnot come from urea, petrolatum or water since the effect is closelysimilar in all three cases. This is completely surprising since DMSO isknown for its quick penetration. Also very surprisingly, is thediscovery that waterless DMSO formulations D50 and D52 have asubstantial moisturizing effect despite the lack of water andadditionally they can ameliorate against after taste and breath odorside effects. Thus, in one or more embodiments there are provided DMSOformulations that are useful in improving skin hydration.

Part D - Aprotic-Alcoholic formulations with 0% 20% and 40% ethanol andFoam Properties % w/w % w/w % w/w Formulation D50 D27 D101 IngredientsDimethyl Sulfoxide 45.00 45.00 45.00 Glycerin (humectant) 15.00 15.00 —Propylene glycol (humectant) 15.00 15.00 6.50 Ethanol 0.00 20.00 40.00Urea 20.00 — — Cetostearyl alcohol 1.50 1.50 3.00 Steareth-2 2.00 2.004.00 Hydroxypropyl cellulose EF 1.50 1.50 1.50 Total 100.00 100.00100.00 Propellant AP-70 8.00 8.00 8.00 Foam properties Foam Quality GoodGood to Poor Excellent Shakability Good Good Good Collapse Time at 36°C. (sec) >180 NM* Immediate *NM: Not Measured

Comments: Formulations D27, D50 and D101 were prepared according to theGeneral Manufacturing Procedures described in the Method/Test section.As can be seen from the above Table Formulations D27 D50, which arewaterless formulations containing up to 20% ethanol provide good toexcellent quality breakable foams. However, when the ethanol contentreaches 40% of the formulation, a clear defoaming effect is observed andno quality foam was produced, unlike as in formulation D101. The aproticalcoholic defoaming effect was observed in the presence of surfactant soit follows that in the absence of surfactant the defoaming effect may beof the same order or more pronounced. So in one or more embodiments thelevel of short chain alcohols, such as, ethanol, is about or less thanabout 35%, is about or less than about 30%; is about or less than about25%, is about or is less than about 20%, is about or is less than about15%, is about or is less than about 10%, is about or is less than about5%.

Example 7—Waterless Foamable Vehicle Compositions Containing DMSO and aHydrophobic Solvent

% w/w Formulations D28 D29 D30 Ingredients Dimethyl Sulfoxide 77.0 73.569.0 Stearyl Alcohol — 3.0 5.0 Glycerol Monostearate 3.0 3.0 5.0Hydroxypropyl methylcellulose K100M — 0.5 1.0 Light Mineral Oil 20.020.0 20.0 Total 100.0 100.0 100.0 Propellant AP-70 10.0 10.0 10.0 FoamProperties Foam Quality Fairly Good Good Good Collapse Time (sec) 90 150>180

Comments: A hydrophobic solvent was added into a mixture of DMSO andglyceryl monostearate. As shown in formulation D28, the addition ofmineral oil to DMSO gave a fairly good quality foam that collapsed after90 sec. In comparison with example D15 (containing DMSO and glycerylmonostearate only), it can be seen that the addition of a hydrophobicsolvent has a defoaming effect.

Formulations D29 and D30 show that, when sufficient amounts of a foamadjuvant and a gelling agent are further added to the components offormulation D28, good quality breakable foam that did not collapse after180 sec can be produced. Thus, in the presence of a hydrophobic solventthe inclusion of additional foam stabilizers to the surfactantsubstantially improves collapse time.

FIG. 3 depicts a microscopic observation of formulation D30 wheredroplets can been seen, showing that mineral oil and dimethyl sulfoxideform an emulsion in the presence of a surface active agent. Dimethylsulfoxide is immiscible with hydrophobic solvents. Thus, it will form awaterless emulsion with hydrophobic solvents with surfactant. Having ahydrophobic solvent present can add to the sensory feeling and help tomaintain skin moisture and oil. Although DMSO can aid penetration ofother ingredients into the skin and mucosal membrane because DMSO is notmiscible per se with hydrophobic solvents it leads to another usefulproperty and advantage; namely that for topical and mucosal body cavityuse, where the formulations are to be repeatedly applied and left on theskin or within the body cavity DMSO should not lead to stripping of theskin or mucosal membrane of oils.

Section B—Aqueous or Water Containing Aprotic Formulations Example8—Compositions Containing 45% Dimethyl Sulfoxide, Water and SurfaceActive Agents

Physical % w/w Formulations HLB state D32 D33 D34 D35 D36 IngredientsDimethyl — Liquid 45.0 45.0 45.0 45.0 75.0 Sulfoxide Water — Liquid 52.052.0 52.0 52.0 20.0 Tween 80 15.0 Liquid 3.0 — — — — Ceteth 20 15.7Solid — 3.0 — — — PEG-100 18.8 Solid — — — — 5.0 Stearate Sorbitan 4.3Liquid — — 3.0 — — Monooleate Glycerol 3.8 Solid — — — 3.0 —Monostearate Total — — 100.0 100.0 100.0 100.0 100.0 Propellant AP-70 —Gas 10.0 10.0 10.0 10.0 8.0 Foam Properties Foam Quality — — ExcellentExcellent Fairly Fair Fairly Good Good Collapse Time (sec) — — 90 75 4520 not measured

Comments: Various different surfactants were dissolved into a mixture ofDMSO and water. As shown in formulation D34 and D35, the addition ofsolid or liquid surfactants of HLB value smaller than 5 does not givesatisfying foams, but either bubbly liquids or very watery foams thatrapidly collapse. This is in contrast to what was observed withwaterless formulations where low HLB solid surfactants with a linearfatty acid and a more polar head were preferred. Glycerol monostearatewhich produces excellent waterless quality foams with DMSO is renderedineffective here by the addition of water. Further, as seen informulation D36, the addition of PEG-100 Stearate, a solid surfactantwith a high HLB value of 18.8 produced a very watery foam. Thus, makingquality foams containing both water and dimethyl sulfoxide is notobvious considering was has been learned above in the production ofwaterless DMSO foams.

However, surprisingly, the addition of liquid or solid surfactants ofHLB value close to 15 such as Tween 80 and Ceteth 20 to the water/DMSOmixture dramatically improves the foam quality. Moreover, this wasachieved without the addition of polymer to stabilize the foam. As shownin formulations D32 and D33, excellent quality breakable foams wereproduced, that did not collapse after 75 to 90 seconds of incubation at36° C. Upon application to a target site and a simple rub of the foamswith the hand, the foams broke, spread evenly over the skin and werereadily absorbed into the skin. Without being bound by any theory it maybe that the range of surfactants which can be applied successfully inaqueous or water containing DMSO formulations is much wider thanavailable for waterless formulations.

Example 9—Compositions Containing from 25% to 75% DMSO

PART A - Formulation containing surfactants % w/w Formulations D36 D38D37 D39 Ingredients Dimethyl Sulfoxide 75.0 75.0 25.0 75.0 Water 20.020.0 70.0 20.0 Poloxamer 188 — 5.0 3.0 3.0 PEG-100 Stearate 5.0 — 2.02.0 Total 100.0 100.0 100.0 100.0 Propellant AP-70 8.0 8.0 8.0 8.0 —Foam Properties Foam Quality Fairly Good Fairly Good Good Good

Comments: Formulations D36 and D38 each of which contained only one foamstabilizing component (PEG-100 Stearate and Poloxamer respectively)provided only fairly good foam quality. However, formulations D37 andD39, which contain at least two foam stabilizing components (Cetostearylalcohol+Poloxamer 407+Methocel K100M; or Poloxamer 188+PEG 100-Stearate)provided good to excellent foam quality. It is interesting to note thatPEG-100 Stearate alone and Poloxamer alone fail to produce foams of goodquality even at 5% by weight (see formulations D36 and D38). However,when these two components are combined, they surprisingly actsynergistically to provide stable and breakable foams of good quality.Thus in one or more embodiments the aprotic foamable compositionscomprise a synergistic combination of surface active agent and a polamerwith surface active agent like properties, such as PEG 100 Stearate andPoloxamer.

PART B - Formulations without surfactant % w/w Formulation D103Ingredients Dimethyl Sulfoxide 76.60 Water 20.00 Stearyl alcohol 3.00Methocel K100M 0.40 Total 100.00 Propellant AP-70 8.00 Foam propertiesFoam Quality Good Shakability Good Collapse Time at 36° C. (sec) 90

Comments: Formulation D103 was prepared according to the GeneralManufacturing Procedures described in the Method/Test section. Thisformulation is an example of an aqueous vehicle containing very highamounts of DMSO, some water, a fatty alcohol, a polymeric agent but nosurfactant. Surprisingly, and despite the absence of surfactant and thehigh aprotic solvent level, a breakable foam of good quality wasobtained which did not collapse for 90 seconds at 36° C.

In one or more embodiments, there is provided a surfactant-free foamformulation comprising DMSO, water, fatty alcohols and polymeric agentswhich provides a breakable foam of good quality. In one or morealternative embodiments there is provided a a surfactant-free foamformulation comprising DMSO, water, and fatty alcohols essentially freeof polymeric agents. In one or more other embodiments there is provideda surfactant-free foam formulation comprising DMSO, water, and polymericagents essentially free of fatty alcohols.

Example 10—Compositions Containing from 19% to 45% DMSO with and withoutDiclofenac as an Active Agent (“API”)

Part A - With and Without API % w/w D40 D42 Formulations (Placebo) D40D41 (Placebo) D42 D43 Ingredients DMSO 45.00 45.00 45.50 45.50 45.5045.50 Water 30.50 29.00 17.90 18.10 19.60 17.90 Glycerin 7.00 7.00 10.7010.80 10.80 10.70 Propylene glycol 5.00 5.00 10.70 10.80 10.80 10.70Ethanol 10.00 10.00 11.20 11.30 11.30 11.20 Cetostearyl alcohol 1.001.00 1.00 0.80 0.80 1.10 Poloxamer 407 1.00 1.00 1.00 — — —Hydroxypropyl 0.50 0.50 0.50 0.40 0.40 0.50 methylcellulose K100M PEG100-Stearate — — — 0.80 0.80 0.90 Diclofenac - sodium — 1.50 1.50 — 1.501.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Propellant AP-708.00 8.00 8.00 8.00 8.00 8.00 Foam Properties Foam Quality ExcellentExcellent Good to Good Good Good to Excellent Excellent Collapse Time(sec) >180 >180 >180 >180 >180 >180 Presence of drug Placebo No NoPlacebo No No crystals

Comments: Formulations D40 to D43 are examples of foam vehicles with andwithout an active agent, containing 45% of DMSO, water, humectants,gelling agents, a foam adjuvant and/or surfactants. Formulations whichcontain at least two foam stabilizing components provided breakablefoams of good to excellent quality that did not collapse after 180 secat 36° C.

It can be noted that the addition of about 10% of ethanol did not appearto affect the foam stability or quality. It can also be noted that theaddition of an active agent did not appear to affect foam quality andstability, and that all these compositions fully dissolve diclofenacsodium. Accordingly, the penetration of the dissolved API should befacilitated by the aprotic solvent DMSO to provide good bioavailability.

Part B - DMSO Carrier Formulation without polymer w/w % FormulationsD100 Ingredients DMSO 45.00 Water 20.00 Ethanol 10.00 Glycerin 10.00Propylene Glycol 10.00 Cetostearyl alcohol 1.25 Polysorbate 80 1.25Ceteth-2 1.25 PEG-100 Stearate 1.25 Total 100.00 Propellant AP-70 10.00Foam Properties Foam Quality Excellent Shakability Good Collapse Time(sec) >180

Comments: Formulation D100 was prepared according to the GeneralManufacturing Procedures described in the Method/Test section. Thisformulation is an example of a foam vehicle without polymer containing45% of DMSO, water, humectant, a foam adjuvant and surfactants that cangenerate excellent quality foam that did not collapse after 180 sec at36° C. The presence of about 10% of ethanol did not appear to affect thefoam quality or the collapse time.

Part C A sample of formulation D40 above was tested for additionalphysical parameters and the results are provided below: Viscosity of thepre-foam formulation (cPs) 146 Density of the foam (g/ml) 0.066 Foam pH(diluted 1:5 with water) 6.01 Mean Bubble Size (micrometers) 69

Comments: Formulation D44 is an example of a foam vehicle containing 19%of DMSO, 50% of water, a hydrophobic solvent, a gelling agent, a foamadjuvant and a surfactant. It can be seen that formulations containing aprotic polar solvent, an aprotic polar solvent, an apolar solvent and asuitable combination of foam stabilizing agents, can provide breakablefoams of good to excellent quality that do not collapse after 180 sec.

PART D - Emulsion with Hydrophobic Solvent w/w % w/w % w/w %Formulations D44 D53 D54 (Placebo) (Placebo) (Placebo) Ingredients DMSO19.00 45.00 45.00 Water 50.00 29.00 35.00 Light Mineral Oil 20.00 15.0015.00 Stearyl Alcohol 5.00 5.00 — Hydroxypropyl methylcellulose 1.001.00 — K100M Glycerol monostearate 5.00 5.00 5.00 Total 100.00 100.00100.00 Propellant AP-70 10.00 10.00 10.00 Foam Properties Foam QualityGood Good Good Collapse Time (sec) >180 >180 >180 Foam Density — 0.1660.213

Comments: All the formulations provide quality foams with satisfactorycollapse times. Surprisingly, there is no apparent change in quality orcollapse on removal of the foam adjuvant and polymer but the density isunexpectedly less when they are present. Without being bound to anytheory, it may be that foam adjuvants and/or polymeric agents can enablea better propellant dissolution within the pressurized formulation, andso an improved expansion upon foam dispensing.

Part E—without Surfactant

See Example 9, Part B from which it was unexpectedly observed that asurfactant-free foam formulation comprising DMSO, water, fatty alcoholsand polymeric agents provides a breakable foam of good quality.

Part F—Manufacture:

Formulation D53:

-   -   1) Mix DMSO and water, Add Methocel K100M at room temperature        and mix until gel formation.    -   2) Heat to 50-60° C., add stearyl alcohol and glycerol        monostearate and mix until dissolution.    -   3) Add slowly light mineral oil and mix until homogeneity is        obtained.    -   4) Cool to room temperature and complete water if necessary to        100%        Formulation D54:    -   1) Mix DMSO and Water.    -   2) Heat to 50-60° C. and add glycerol monostearate while mixing        to dissolution.    -   3) & 4) As above.

Example 11—Foamable Vehicle Compositions Containing 45% of AproticSolvent

Part A - Various other examples of aprotic solvents % w/w FormulationsD45 D46 D47 Ingredients Acetone 45.00 — — Acetonitrile — 45.00 — DMF — —45.00 Water 30.50 30.50 30.50 Glycerin 7.00 7.00 7.00 Propylene glycol5.00 5.00 5.00 Ethanol 10.00 10.00 10.00 Cetostearyl alcohol 1.00 1.001.00 Poloxamer 407 1.00 1.00 1.00 Hydroxypropyl methylcellulose 0.500.50 0.50 K100M Total 100.00 100.00 100.00 Propellant AP-70 8.00 8.008.00 Foam Properties Foam Quality Good Good Excellent Collapse Time(sec) >180 120 >180

Comments: Formulations D45 to D47 are examples of foam vehiclescontaining 45% of a polar aprotic solvent, ethanol, water, humectants,gelling agents and a foam adjuvant. The polar aprotic solvents usedcomprise acetone, acetonitrile and dimethyl formamide. The threeformulations provided breakable foams of good to excellent quality thatdid not collapse after 120 to 180 sec at 36° C., showing that thepresent invention includes a range of polar aprotic solvents. It can benoted that the addition of about 10% of ethanol did not appear to affectthe foam stability or quality.

Part B - Aprotic-hydroalcoholic formulations with 10%; 11.3% and 40%Alcohol % w/w % w/w % w/w Formulations D40 D42 D102 (Placebo) (Placebo)(Placebo) DMSO 45.00 45.50 30.00 Water 30.50 18.10 15.00 Glycerin 7.0010.80 — Propylene glycol 5.00 10.80 6.50 Ethanol 10.00 11.30 40.00Cetostearyl alcohol 1.00 0.80 3.00 Poloxamer 407 1.00 — — Hydroxypropyl0.50 0.40 — methylcellulose K100M PEG 100-Stearate — 0.80 — Steareth-2 —— 4.00 Hydroxypropyl — — 1.50 cellulose EF Total 100.00 100.00 100.00Propellant AP-70 8.00 8.00 8.00 Foam Properties Foam Quality ExcellentGood Excellent Collapse Time (sec) >180 >180 60

Comments: Formulations D40, D42 and D102 were prepared according to theGeneral Manufacturing Procedures described in the Method/Test section.All these aprotic-aqueous formulations produced a foam of quality.Formulation D102 is an example of aqueous foam containing 30% DMSO, ahumectant, a fatty alcohol, a polymer and a surfactant, with a highethanol content of 40% which surprisingly generated a foam of excellentquality. Due to the high ethanol content of D102, the collapse time isshorter than in formulations D40 and D42, but remains essentiallysatisfactory. In complete contrast, as can be seen in Example 6 Part D,a similar non-aqueous formulation with 40% alcohol did not produce afoam. Thus, it follows that Aprotic—hydroalcoholic formulations are moreresilient than their non-aqueous counterparts and that the presence of arelatively small amount of water aids in the quality and orstabilization of the resultant foam.

Section C—Usability Testing Example 12—Comparative Tolerability andAcceptability Study of a Waterless Foam DMSO Composition Vs. AqueousFoam DMSO Composition

A panel of three testers was asked to apply on their hand an aqueousDMSO foam preparation and a waterless DMSO foam preparation. Thewaterless formulation was D15 (see Example 3 above) and the aqueousformulation was D33 (see Example 8 above).

Each was asked to describe their feelings about the ease of application,skin feeling and penetrability of each of the products.

Both formulations were described as having a good appearance and anexcellent ease of application and penetration speed into the skin uponslight rubbing. Testers added that the aqueous formulation has a veryslight greasy feeling on skin, and the waterless formulation has aslight greasy feeling on skin. In both cases, the greasy feelingdisappeared after 10 to 20 seconds. Testers did not report anyafter-taste or bad breath after application. It may be a furtherunexpected advantage of DMSO foams that such side effects are absent orameliorated due to the low density of the foam—allowing small amounts tobe spread over a target area—and or due to the composition offormulation.

Section D—Packaging Compatibility

Part A—Background

Aprotic solvents, such as, DMSO have outstanding solvent properties,being able to dissolve a wide range of organic and inorganic compounds,including plastics, resins and alloys used in fabrication of canistersand valve parts. Therefore, packaging components for holding anddelivering such solvents can readily corrode and/or deteriorateespecially when high concentrations are present in the compositions, asdisclosed in the present foam formulations.

Aerosol packaging is primarily composed of a coated canister, a valve,an actuator and optionally a dip-tube. The components being in prolongedcontact with the formulations are mainly the canister internal coatingand valve parts (cup and housing). In the following study thecompatibility of various packaging components with highly concentratedDMSO solution was assessed in the absence of propellant.

Part B—Procedure

The tested packaging components are incubated in contact with a solutionof DMSO in water (50:50 w/w) during up to six months at 50° C. At thedesired time-points, the packaging components are removed from theincubators, canisters are opened and a visual observation is performedto determine the presence deterioration, corrosion, peeling, scratches,etc that may result from the prolonged contact with the DMSO solution.

Part C—Compatibility Results

An aluminum canister with a polyimide amide (PAM) internal coating wasfilled with a solution of DMSO in water (50:50 w/w), crimped with anepoxy coated valve having a dip-tube and incubated at 50° C.

Incubation Canister conditions coating Valve cup Valve housing Dip-tube1M 50° C. no change no change slight change in color no change 2M 50° C.no change no change color became pale yellow no change 3M 50° C. nochange no change color became pale yellow no change 6M 50° C. no changeno change color became yellow no change

Surprisingly, no canister deterioration was observed, even after 6months at 50° C. No corrosion or deterioration was observed in the valvecup and in the dip-tube. Only a minor change in color of the valvehousing was observed, which is acceptable and not considered asdeterioration.

However, a canister with an internal coating made of phenol epoxy andcontaining formulation D22 showed signs of corrosion after 6 months atroom temperature. The valve cup and housing though was of epoxy type anddid not show any sign of corrosion. There was no diptube in thiscanister. So over time during storage canisters, for example, withphenol epoxy coatings can display corrosion and deterioration.

In one or more embodiments, there is provided a kit comprising anaerosol canister, a valve, an actuator, optionally a dip-tube, and aDMSO foam formulation, wherein the packaging components are compatiblewith a formulation containing DMSO, and wherein essentially no corrosionor deterioration is observed. In one or more embodiments the canistersare essentially free of corrosion and or deterioration for 1 month, or 2months or for 3 months or for 6 months or for 12 months or for 18 monthsor for 24 months at room temperature. In one or more further embodimentsthe canisters are essentially free of corrosion and or deterioration for1 month, or for 2 months, or for 3 months, or for 6 months, or for 12months, or for 18 months, or for 24 months at 40° C. In one or morefurther embodiments the canisters are essentially free of corrosion andor deterioration for 1 month, or 2 months or for 3 months, or for 6months, or for 12 months, or for 18 months, or for 24 months at 50° C.In one or more other embodiments any corrosion and or deteriorationobserved was not of significance. In one or more embodiments anycorrosion and or deterioration observed in the canisters was not ofsignificance for 1 month, or for 2 months, or for 3 months, or for 6months, or for 12 months, or for 18 months, or for 24 months at roomtemperature. In one or more further embodiments any corrosion and ordeterioration observed in the canisters was not of significance for 1month, or for 2 months, or for 3 months, or for 6 months, or for 12months, or for 18 months, or for 24 months at 40° C. In one or morefurther embodiments any corrosion and or deterioration observed in thecanisters was not of significance for 1 month, or for 2 months, or for 3months, or for 6 months, or for 12 months, or for 18 months, or for 24months at 50° C.

Part D—Can in Can

Background: A bag in can can be used in three basic ways withpropellant, namely, a) with the propellant not in the bag and beingseparate from the formulation in the bag; b) with propellant present inthe formulation in the bag only; c) with propellant both in the bag andoutside of the bag. In case a) without surfactant the formulation islikely to exit as a gel or fluid. In cases b) and c) the formulation canfoam. The propellant outside the bag is to expel the contents of thebag. The propellant within the formulation in the bag is to generatefoam. When the formulation is primarily expelled by propellant outsidethe bag then the amount of propellant in the formulation can influencefoam properties, such as, density.

An aluminum can-in-can canister with a phenol epoxy internal coating wasfilled with a solution of DMSO in water (50:50 w/w), crimped with anepoxy coated valve without dip-tube and incubated for one month at 50°C.

After opening of the canister, no corrosion or deterioration wasobserved neither on the canister internal coating, nor on the differentvalve parts.

In one or more embodiments, there is provided a kit comprising acan-in-can aerosol canister, a valve, an actuator, optionally adip-tube, and a DMSO foam formulation, wherein the packaging componentsare compatible with a formulation containing DMSO, and wherein nocorrosion or deterioration is observed. In one or more embodiments thecanisters are essentially free of corrosion and or deterioration for 1month, or 2 months or for 3 months or for 6 months or for 12 months orfor 18 months or for 24 months at room temperature. In one or morefurther embodiments the canisters are essentially free of corrosion andor deterioration for 1 month, or for 2 months, or for 3 months, or for 6months, or for 12 months, or for 18 months, or for 24 months at 40° C.In one or more further embodiments the canisters are essentially free ofcorrosion and or deterioration for 1 month, or 2 months or for 3 months,or for 6 months, or for 12 months, or for 18 months, or for 24 months at50° C. In one or more other embodiments any corrosion and ordeterioration observed was not of significance. In one or moreembodiments any corrosion and or deterioration observed in the canisterswas not of significance for 1 month, or for 2 months, or for 3 months,or for 6 months, or for 12 months, or for 18 months, or for 24 months atroom temperature. In one or more further embodiments any corrosion andor deterioration observed in the canisters was not of significance for 1month, or for 2 months, or for 3 months, or for 6 months, or for 12months, or for 18 months, or for 24 months at 40° C. In one or morefurther embodiments any corrosion and or deterioration observed in thecanisters was not of significance for 1 month, or for 2 months, or for 3months, or for 6 months, or for 12 months, or for 18 months, or for 24months at 50° C.

What is claimed is:
 1. A foam able composition formulated foradministration to the skin comprising a carrier composition comprising:a) a short chain alcohol comprising ethanol present at a concentrationof at least 55% by weight of the carrier; b) about 2% to about 50% byweight of the carrier of a protic polar solvent comprising propyleneglycol; c) a polymeric agent comprising a cellulose ether, wherein thecellulose ether is a hydroxypropyl cellulose present at a concentrationof about 0.5% to about 1% by weight of the carrier; d) a modulatingagent comprising an antioxidizing agent present at a concentration ofabout 0.1% to about 10% by weight of the carrier; e) a metal; f) anessential oil; and g) tetracycline in a therapeutically effective amountof about 1% to about 5% by weight of the carrier, wherein thecomposition is surfactant free, nonaqueous, and tree or essentially freeof fatty alcohol.
 2. The foamable composition of claim 1, wherein theprotic polar solvent is at a concentration of about 12% to about 30% byweight of the carrier.
 3. The foamable composition of claim 1, furthercomprising a liquefied or compressed gas propellant present at aconcentration of about 3% to about 25% by weight of the foamablecomposition.
 4. A foamable composition formulated for administration tothe skin comprising a carrier composition comprising: a) a short chainalcohol comprising ethanol; b) about 12% to about 30% by weight of thecarrier of a protic polar solvent comprising propylene glycol; c) apolymeric agent comprising a cellulose ether; d) a modulating agentcomprising an antioxidizing agent; e) a metal; f) an essential oil; andg) tetracycline in a therapeutically effective amount of about 1% toabout 5% by weight of the carrier, wherein the composition is surfactantfree, nonaqueous, and free or essentially free of fatty alcohol.
 5. Thefoamable composition of claim 4, wherein the short chain alcohol ispresent at a concentration of at least 55% by weight of the carrier. 6.The foamable composition of claim 4, wherein the cellulose ether is ahydroxypropyl cellulose.
 7. The foamable composition of claim 4, whereinthe cellulose ether is present in a concentration of about 0.5% to about1% by weight of the carrier.
 8. The foamable composition of claim 4,wherein the modulating agent is present at a concentration of about 0.1%to about 10% by weight of the carrier.
 9. The foamable composition ofclaim 4, further comprising a liquefied or compressed propellant at aconcentration of about 3% to about 25% by weight of the foamablecomposition.